Frontiers in Immunology

Anti-Mesothelin CAR-NK cells as a novel targeted therapy against cervical cancer

Resistance to the currently available treatment paradigms is one of the main factors that contributes to poor outcomes in patients with advanced cervical cancer. Novel targeted therapy approaches might enhance the patient’s treatment outcome and are urgently needed for this malignancy. While chimeric-antigen receptor (CAR)-based adoptive immunotherapy displays a promising treatment strategy for liquid cancers, their use against cervical cancer is largely unexplored. This study used alpharetroviral SIN vectors to equip natural killer (NK) cells with a third-generation CAR (including CD28 and 4-1BB co-stimulatory domains) targeting Mesothelin, which was identified to be highly expressed on primary human cervical cancer tissues and cervical cancer cell lines in this and other studies. Anti-Mesothelin CAR-NK cells demonstrated high cytotoxicity against cervical cancer cells in 2D and 3D culture models, which corresponded to increased degranulation of CAR-NK-92 cells upon exposure to Mesothelin+ target cells. Mesothelin- cervical cancer cells were generated by CRISPR-Cas9-mediated knockout and used to show target antigen specificity of anti-Mesothelin CAR-NK-92 cells and primary NK cells derived from different healthy donors in co-culture experiments. Combination of anti-Mesothelin CAR-NK-92 cells with chemotherapy revealed increased elimination of cancer cells as compared to monotherapy settings. Our findings indicate the promise of anti-Mesothelin CAR-NK cells as a potential treatment option against cervical cancer, as well as other Mesothelin+ malignancies.

Prognostic model of ubiquitination-related genes in ovarian cancer based on transcriptomic analysis and experimental validation

ObjectiveUbiquitination plays a crucial role in the malignant progression of ovarian cancer. With the advent of proteolysis-targeting chimeras (PROTACs) targeting ubiquitin enzymes, precision therapies are now possible. Therefore, it is imperative to ascertain the prognostic significance of ubiquitination-related genes in ovarian cancer.MethodsA prognostic model based on ubiquitination-related genes was developed using data from TCGA and GTEx databases. Performance was assessed via Kaplan-Meier, ROC curves, and Cox regression; a nomogram was created. The model’s stability was checked using training and test sets. FBXO45 was also experimentally validated in ovarian cancer.ResultsThe model, based on 17 genes related to ubiquitination, showed high performance (1-year AUC = 0.703, 3-year AUC = 0.704, 5-year AUC = 0.705). The high-risk group had significantly lower overall survival (P < 0.05). Immune analysis showed higher levels of CD8+ T (P < 0.05), M1 (P < 0.01) and follicular (P < 0.05) cells in the low-risk group. High-risk patients had more mutations in MUC17 and LRRK2, while low-risk patients had more RYR2 mutations. FBXO45 is a key E3 ubiquitin ligase in ovarian cancer, promoting growth, spread and migration via the Wnt/β-catenin pathway.ConclusionUbiquitination-related markers provide reliable prognostic insights and reflect the immune microenvironment in ovarian cancer, offering a basis for clinical targeting strategies.

Deciphering the immune landscape dominated by cancer-associated fibroblasts to investigate their potential in indicating prognosis and guiding therapeutic regimens in high grade serous ovarian carcinoma

Limited immunotherapeutic effect in high-grade serous ovarian carcinoma (HGSOC) propels exploration of the mechanics behind this resistance, which may be partly elucidated by investigating characters of cancer-associated fibroblasts (CAFs), a significant population in HGSOC involved in shaping tumor immune microenvironment. Herein, leveraging gene expression data of HGSOC samples from The Cancer Genome Atlas and Gene Expression Omnibus datasets, we suggested that CAFs detrimentally affected the outcomes of HGSOC patients. Subsequently, we performed weighted gene co-expression network analysis (WGCNA) to identify a CAFs-related module and screened out seven hub genes from this module, all of which were positively correlated with the infiltration of immunosuppressive macrophages. As one of the hub genes, the expression of fibrillin 1 (FBN1) and its relevance to CD206 were further verified by immunohistochemistry staining in HGSOC samples. Meanwhile, we extracted genes that correlated well with CAF signatures to construct a CAFscore. The capacity of the CAFscore as an independent prognostic factor was validated by Cox regression analyses, and its relevance to components as well as signals in the tumor immune microenvironment was also investigated. Under the evaluation by the CAFscore, HGSOC patients with relatively high CAFscore had worse outcomes, activated mesenchymal signaling pathways, and immune checkpoint blockade (ICB) resistance signatures, which was consistent with the fact that non-responders in anti-PD-1 treatment cohorts tended to have higher CAFscore. Besides, the possibility of CAFscore to guide the selection of sensitive chemotherapeutic agents was explored. In conclusion, individualized assessment of the CAFscore could uncover the extent of stroma activation and immunosuppression and inform therapeutic strategies to improve the benefit of therapies.

Research progress on the mechanism of glycolysis in ovarian cancer

Glycolysis is the preferred energy metabolism pathway in cancer cells even when the oxygen content is sufficient. Through glycolysis, cancer cells convert glucose into pyruvic acid and then lactate to rapidly produce energy and promote cancer progression. Changes in glycolysis activity play a crucial role in the biosynthesis and energy requirements of cancer cells needed to maintain growth and metastasis. This review focuses on ovarian cancer and the significance of key rate-limiting enzymes (hexokinase, phosphofructokinase, and pyruvate kinase, related signaling pathways (PI3K-AKT, Wnt, MAPK, AMPK), transcription regulators (HIF-1a), and non-coding RNA in the glycolytic pathway. Understanding the relationship between glycolysis and these different mechanisms may provide new opportunities for the future treatment of ovarian cancer.

Glycan dysregulation as one of major metabolic subtypes is associated with TERC overexpression and poor outcomes in cervical cancer

BackgroundMetabolic reprogramming is an important hallmark of cervical cancer (CC), and extensive studies have provided important information for translational and clinical oncology. Here we sought to determine metabolic association with molecular aberrations, telomere maintenance and outcomes in CC.MethodsRNA sequencing data from TCGA cohort of CC was analyzed for their metabolic gene expression profile and consensus clustering was then performed to classify tumors into different groups/subtypes. The reproducibility of the classification system was further evaluated in GSE68339 CC cohort. The association of metabolic groups with clinical characteristics, telomere maintenance and somatic alterations was assessed to define molecular features of each subtype. Finally, the metabolomic analyses were carried out to directly measure metabolites in tumors and their non-tumorous adjacent tissues (NTs) from 10 CC patients using ultra performance liquid chromatography-mass spectrometry (UPLC-MS).ResultsThe analysis of 2752 metabolism-related gene expression in TCGA 304 CC tumors showed a significant expression heterogeneity of these genes. Consensus clustering of these CC tumors identified three distinct metabolic groups (MG), with MG1, MG2 and MG3 characterized by dysregulations in glycans, amino acids/carbohydrates and lipids, respectively. Patients within the MG1 subtype had the shortest disease-free survival (DFS) coupled with robust TERC overexpression. This metabolic stratification was validated in the GSE68339 CC cohort. We further developed a 3 glycan-related gene model (GRGM-3) as a predictor for patient DFS. The TCGA patients were divided into risk-Low and High groups based on their tumor GRGM-3 score using a median cutoff, and those in the risk-High group had significantly shorter DFS. When combined with TERC expression, patients in the high-risk group with high TERC levels had the shortest DFS. Finally, we analyzed metabolites in tumors and NTs from 10 CC patients and further confirmed the metabolic dysregulations identified by gene expression profiling.ConclusionMetabolic heterogeneity occurs substantially in CCs and glycan dysregulation is associated with the shortest DFS in CCs. Specifically, the combination of GRGM-3 scores with TERC expression identifies patients with the poorest outcomes, providing a potential tool for individualized risk assessment and contributing to CC precision medicine. It is worth validating our findings for potential clinical application.

Knowledge mapping of immunotherapy in cervical carcinoma: a bibliometric analysis (2000-2023)

BackgroundCervical carcinoma is a type of malignant tumor that primarily develops in the cervix, the lower part of the uterus. In recent years, Despite the considerable progress made in immunotherapy research for cervical carcinoma, an important aspect has been largely overlooked - the absence of a comprehensive bibliometric analysis in this field. By employing bibliometric techniques, this study aims to fill this gap and provide a comprehensive overview of the knowledge structure and research hotspots within the realm of immunotherapy in cervical carcinoma.MethodA comprehensive search was conducted on the web of science core collection(WoSCC) database to identify publications related to immunotherapy specifically for the treatment of cervical carcinoma. The search spanned the period from the year 2000 to 2023. Several analytical tools were employed. These included VOSviewers, CiteSpace, and the R package “bibliometrix”.ResultsA total of 654 research articles from 66 different countries have been included in the analysis. The United States and China have emerged as the leading countries in publishing research on immunotherapy in cervical carcinoma. Leiden University and Memorial Sloan-Kettering Cancer Center from the Netherlands and the United States respectively have a close cooperation. Fudan University from China and the German Cancer Research Center are also among the key institutions leading research in this area. Frontiers in Oncology has emerged as the most popular and widely recognized publication in the field of immunotherapy in cervical carcinoma. Journal of Clinical Oncology is frequently cited by researchers in this area. Van Der Burg, Sjoerd H has published the highest number of papers. Tewari, Krishnansu S has been the most co-cited author. Keywords such as PD-L1, chemotherapy, and immune checkpoint inhibitors have gained significant attention in recent years.ConclusionThis is the first bibliometric study that comprehensively summarizes the research trends and developments of immunotherapy in cervical carcinoma. This groundbreaking study not only summarizes the current research trends and developments in immunotherapy for cervical carcinoma but also provides a reference for scholars studying the treatment of cervical cancer.

Single-cell RNA sequencing and immune microenvironment analysis reveal PLOD2-driven malignant transformation in cervical cancer

BackgroundCervical cancer is the fourth most common cancer in women globally, and the main cause of the disease has been found to be ongoing HPV infection. Cervical cancer remains the primary cause of cancer-related death despite major improvements in screening and treatment approaches, especially in low- and middle-income nations. Therefore, it is crucial to investigate the tumor microenvironment in advanced cervical cancer in order to identify possible treatment targets.Materials and methodsIn order to better understand malignant cervical cancer epithelial cells (EPCs), this study used bulk RNA-seq data from UCSC in conjunction with single-cell RNA sequencing data from the ArrayExpress database. After putting quality control procedures into place, cell type identification and clustering analysis using the Seurat software were carried out. To clarify functional pathways, enrichment analysis and differential gene expression were carried out. The CIBERSORT and ESTIMATE R packages were used to evaluate the immune microenvironment characteristics, and univariate and multivariate Cox regression analyses were used to extract prognostic features. Furthermore, assessments of drug sensitivity and functional enrichment were carried out.ResultsEight cell types were identified, with EPCs showing high proliferative and stemness features. Five EPC subpopulations were defined, with C1 NNMT+ CAEPCs driving tumor differentiation. A NNMT CAEPCs Risk Score (NCRS) model was developed, revealing a correlation between elevated NCRS scores and adverse patient outcomes characterized by immune evasion. In vitro experiments validated that the prognostic gene PLOD2 significantly enhances proliferation, migration, and invasion of cervical cancer cells.ConclusionThis investigation delineated eight cell types and five subpopulations of malignant EPCs in cervical cancer, establishing the C1 NNMT+ CAEPCs as a crucial therapeutic target. The NCRS model demonstrated its prognostic capability, indicating that higher scores are associated with poorer clinical outcomes. The validation of PLOD2 as a prognostic gene highlights its therapeutic potential, underscoring the critical need for integrating immunotherapy and targeted treatment strategies to enhance diagnostic and therapeutic approaches in cervical cancer.

Simultaneous targeting of Tim3 and A2a receptors modulates MSLN-CAR T cell antitumor function in a human cervical tumor xenograft model

IntroductionChimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies. However, its efficacy in solid tumors is limited by the immunosuppressive tumor microenvironment that compromises CAR T cell antitumor function in clinical settings. To overcome this challenge, researchers have investigated the potential of inhibiting specific immune checkpoint receptors, including A2aR (Adenosine A2 Receptor) and Tim3 (T cell immunoglobulin and mucin domain-containing protein 3), to enhance CAR T cell function. In this study, we evaluated the impact of genetic targeting of Tim3 and A2a receptors on the antitumor function of human mesothelin-specific CAR T cells (MSLN-CAR) in vitro and in vivo.MethodsSecond-generation anti-mesothelin CAR T cells were produced using standard cellular and molecular techniques. A2aR-knockdown and/or Tim3- knockdown anti-mesothelin-CAR T cells were generated using shRNA-mediated gene silencing. The antitumor function of CAR T cells was evaluated by measuring cytokine production, proliferation, and cytotoxicity in vitro through coculture with cervical cancer cells (HeLa cell line). To evaluate in vivo antitumor efficacy of manufactured CAR T cells, tumor growth and mouse survival were monitored in a human cervical cancer xenograft model.ResultsIn vitro experiments demonstrated that knockdown of A2aR alone or in combination with Tim3 significantly improved CAR T cell proliferation, cytokine production, and cytotoxicity in presence of tumor cells in an antigen-specific manner. Furthermore, in the humanized xenograft model, both double knockdown CAR T cells and control CAR T cells could effectively control tumor growth. However, single knockdown CAR T cells were associated with reduced survival in miceConclusionThese findings highlight the potential of concomitant genetic targeting of Tim3 and A2a receptors to augment the efficacy of CAR T cell therapy in solid tumors. Nevertheless, caution should be exercised in light of our observation of decreased survival in mice treated with single knockdown MSLN-CAR T cells, emphasizing the need for careful efficacy considerations.

Immunological modifications following chemotherapy are associated with delayed recurrence of ovarian cancer

IntroductionOvarian cancer recurs in most High Grade Serous Ovarian Cancer (HGSOC) patients, including initial responders, after standard of care. To improve patient survival, we need to identify and understand the factors contributing to early or late recurrence and therapeutically target these mechanisms. We hypothesized that in HGSOC, the response to chemotherapy is associated with a specific gene expression signature determined by the tumor microenvironment. In this study, we sought to determine the differences in gene expression and the tumor immune microenvironment between patients who show early recurrence (within 6 months) compared to those who show late recurrence following chemotherapy.MethodsPaired tumor samples were obtained before and after Carboplatin and Taxol chemotherapy from 24 patients with HGSOC. Bioinformatic transcriptomic analysis was performed on the tumor samples to determine the gene expression signature associated with differences in recurrence pattern. Gene Ontology and Pathway analysis was performed using AdvaitaBio’s iPathwayGuide software. Tumor immune cell fractions were imputed using CIBERSORTx. Results were compared between late recurrence and early recurrence patients, and between paired pre-chemotherapy and post-chemotherapy samples.ResultsThere was no statistically significant difference between early recurrence or late recurrence ovarian tumors pre-chemotherapy. However, chemotherapy induced significant immunological changes in tumors from late recurrence patients but had no impact on tumors from early recurrence patients. The key immunological change induced by chemotherapy in late recurrence patients was the reversal of pro-tumor immune signature.DiscussionWe report for the first time, the association between immunological modifications in response to chemotherapy and the time of recurrence. Our findings provide novel opportunities to ultimately improve ovarian cancer patient survival.

Adaptive transcriptomic and immune infiltrate responses in the tumor immune microenvironment following neoadjuvant chemotherapy in high grade serous ovarian cancer reveal novel prognostic associations and activation of pro-tumorigenic pathways

The high rate of ovarian cancer recurrence and chemoresistance necessitates further research into how chemotherapy affects the tumor immune microenvironment (TIME). While studies have shown that immune infiltrate increases following neoadjuvant (NACT) chemotherapy, there lacks a comprehensive understanding of chemotherapy-induced effects on immunotranscriptomics and cancer-related pathways and their relationship with immune infiltrate and patient responses. In this study, we performed NanoString nCounter® PanCancer IO360 analysis of 31 high grade serous ovarian cancer (HGSOC) patients with matched pre-treatment biopsy and post-NACT tumor. We observed increases in pro-tumorigenic and immunoregulatory pathways and immune infiltrate following NACT, with striking increases in a cohort of genes centered on the transcription factors ATF3 and EGR1. Using quantitative PCR, we analyzed several of the top upregulated genes in HGSOC cell lines, noting that two of them, ATF3 and AREG, were consistently upregulated with chemotherapy exposure and significantly increased in platinum resistant cells compared to their sensitive counterparts. Furthermore, we observed that pre-NACT immune infiltrate and pathway scores were not strikingly related to platinum free interval (PFI), but post-NACT immune infiltrate, pathway scores, and gene expression were. Finally, we found that higher levels of a cohort of proliferative and DNA damage-related genes was related to shorter PFI. This study underscores the complex alterations in the ovarian TIME following chemotherapy exposure and begins to untangle how immunologic factors are involved in mediating chemotherapy response, which will allow for the future development of novel immunologic therapies to combat chemoresistance.

Interleukin-6 and indoleamine-2,3-dioxygenase as potential adjuvant targets for Papillomavirus-related tumors immunotherapy

High-risk Human papillomavirus (HPV) infections represent an important public health issue. Nearly all cervical malignancies are associated with HPV, and a range of other female and male cancers, such as anogenital and oropharyngeal. Aiming to treat HPV-related tumors, our group developed vaccines based on the genetic fusion of the HSV-1 glycoprotein D (gD) with the HPV-16 E7 oncoprotein (gDE7 vaccines). Despite the promising antitumor results reached by gDE7 vaccines in mice, combined therapies may increase the therapeutic effects by improving antitumor responses and halting immune suppressive mechanisms elicited by tumor cells. Considering cancer immunosuppressive mechanisms, indoleamine-2,3-dioxygenase (IDO) enzyme and interleukin-6 (IL-6) stand out in HPV-related tumors. Since IL-6 sustained the constitutive IDO expression, here we evaluated the therapeutic outcomes achieved by the combination of active immunotherapy based on a gDE7 protein-based vaccine with adjuvant treatments involving blocking IDO, either by use of IDO inhibitors or IL-6 knockout mice. C57BL/6 wild-type (WT) and transgenic IL-6-/- mice were engrafted with HPV16-E6/E7-expressing TC-1 cells and treated with 1-methyl-tryptophan isoforms (D-1MT and DL-1MT), capable to inhibit IDO. In vitro, the 1MT isoforms reduced IL-6 gene expression and IL-6 secretion in TC-1 cells. In vivo, the multi-targeted treatment improved the antitumor efficacy of the gDE7-based protein vaccine. Although the gDE7 immunization achieves partial tumor mass control in combination with D-1MT or DL-1MT in WT mice or when administered in IL-6-/- mice, the combination of gDE7 and 1MT in IL-6-/- mice further enhanced the antitumor effects, reaching total tumor rejection. The outcome of the combined therapy was associated with an increased frequency of activated dendritic cells and decreased frequencies of intratumoral polymorphonuclear myeloid-derived suppressor cells and T regulatory cells. In conclusion, the present study demonstrated that IL-6 and IDO negatively contribute to the activation of immune cells, particularly dendritic cells, reducing gDE7 vaccine-induced protective immune responses and, therefore, opening perspectives for the use of combined strategies based on inhibition of IL-6 and IDO as immunometabolic adjuvants for immunotherapies against HPV-related tumors.

Immune profiling of pediatric germ cell tumors identifies key cell populations and novel therapeutic targets

IntroductionPediatric germ cell tumors (GCTs) are rare malignancies, comprising only about 3% of childhood cancers. Despite surgery and platinum-based chemotherapy being mainstays of treatment, their effectiveness varies by tumor subtype, and long-term toxicities remain a concern. We therefore explored the immune landscape of pediatric GCTs to uncover subtype-specific immunological features and identify potential immunotherapeutic targets.MethodsThis retrospective study investigated the immune landscape of pediatric GCTs, utilizing a cohort of 17 patients, including 14 extracranial GCTs (11 ovarian, 3 testicular), three central nervous system (CNS) mixed tumors and four non-neoplastic tissues (controls).ResultsImmune profiling revealed distinct immune microenvironments across the GCT subtypes. Dysgerminomas exhibited an immune-active profile with elevated levels of T cells, CD8+ T cells, and cytotoxic cells, alongside upregulation of immune checkpoints CTLA4, TIGIT, and IDO1, suggesting potential responsiveness to checkpoint inhibitors. In contrast, yolk sac tumors displayed an immunosuppressive environment with high CD24 and PVR expression, indicative of unique immune evasion mechanisms. Embryonal carcinomas also showed high CD24 expression. An in silico analysis of adult GCTs highlighted similarities and differences with pediatric cases; IDO1 and CD24 were consistently upregulated across age groups, while CTLA4 and PVR showed variation.ConclusionOverall, this study provides new insights into pediatric GCT immunology, supporting the potential for tailored immunotherapeutic strategies targeting the distinct immune profiles of pediatric GCT histologies.

Efficacy and safety of natural killer cell therapy in patients with solid tumors: a systematic review and meta-analysis

IntroductionIn 2020, global cancer statistics reported 19.3 million new cases and 10 million deaths annually, highlighting the urgent need for effective treatments. Current therapies, such as surgery, radiation, and chemotherapy, have limitations in comprehensively addressing solid tumor. Recent advances in cancer biology and immuno-oncology, including CAR-T cell therapy, show promise but face efficacy challenges against solid tumors.MethodsThis meta-analysis systematically reviewed studies from PubMed, Embase, Cochrane, and ClinicalTrials.gov databases up to May 2024 to evaluate the clinical efficacy and safety of unmodified NK cell therapies in solid tumors. The included trials focused on reporting objective response rates (ORR).ResultsThirty-one trials involving 600 patients across various cancers (e.g., NSCLC, HCC, breast, ovarian) were analyzed. NK cell therapies demonstrated promising ORRs, particularly 72.3% in hepatocellular carcinoma, often in combination with local therapies. Safety profiles were favorable, with fatigue being the most common adverse event.DiscussionNK cell therapies represent a promising treatment option for solid tumors, offering a viable alternative to genetically modified cell therapies like CAR-T. Further research is needed to optimize the clinical utility of NK cell therapy and integrate it effectively into standard cancer treatment regimens.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023438410, identifier CRD42023438410.

Explore the expression of mitochondria-related genes to construct prognostic risk model for ovarian cancer and validate it, so as to provide optimized treatment for ovarian cancer

BackgroundThe use of gene development data from public database has become a new starting point to explore mitochondrial related gene expression and construct a prognostic prediction model of ovarian cancer.MethodsData were obtained from the TCGA and ICGC databases, and the intersection with mitochondrial genes was used to obtain the differentially expressed genes. q-PCR, Cox proportional risk regression, minimal absolute contraction and selection operator regression analysis were performed to construct the prognostic risk model, and ROC curve was used to evaluate the model for centralized verification. The association between risk scores and clinical features, tumor mutation load, immune cell infiltration, macrophage activation analysis, immunotherapy, and chemosensitivity was further evaluated.ResultsA prognostic risk score model for ovarian cancer patients was constructed based on 12 differentially expressed genes. The score was highly correlated with ovarian cancer macrophage infiltration and was a good predictor of the response to immunotherapy. M1 and M2 macrophages in the ovarian tissue in the OV group were significantly activated, providing a reference for the study of the polarity change of tumor-related macrophages for the prognosis and treatment of ovarian cancer. In terms of drug sensitivity, the high-risk group was more sensitive to vinblastine, Acetalax, VX-11e, and PD-0325901, while the low-risk group was more sensitive to Sabutoclax, SB-505124, cisplatin, and erlotinib.ConclusionThe prognostic risk model of ovarian cancer associated to mitochondrial genes built on the basis of public database better evaluated the prognosis of ovarian cancer patients and guided individual treatment.

Beyond CAR-T Cells: exploring CAR-NK, CAR-M, and CAR-γδ T strategies in solid tumor immunotherapy

Adoptive cell therapy (ACT) employing chimeric antigen receptor (CAR) engineering represents a transformative advancement in cancer immunotherapy. CAR-T cell therapies have demonstrated significant clinical success in hematological malignancies, yet their application to solid tumors faces persistent challenges. Key limitations include the paucity of tumor-specific antigens, poor intratumoral infiltration, immunosuppressive tumor microenvironment (TME), and treatment-related toxicities such as cytokine release syndrome (CRS) and neurotoxicity. In contrast, CAR natural killer (CAR-NK) cells show promise in solid tumors such as ovarian, pancreatic, and glioblastoma, with encouraging preclinical and early clinical evidence, although limited persistence and antigen heterogeneity remain major challenges. Unlike CAR-T cells, CAR-NK therapies mediate tumor clearance through both cytotoxic (e.g., granzyme/perforin release) and cytokine-mediated mechanisms while mitigating toxicity risks. Their lack of human leukocyte antigen (HLA) dependency enables “off-the-shelf” manufacturing from allogeneic donors, circumventing patient-specific production bottlenecks. CAR-macrophage (CAR-M) therapies further address solid tumor barriers by leveraging innate phagocytic clearance, antigen-presenting functions, and TME penetration. Macrophages inherently infiltrate hypoxic tumor regions and remodel stromal barriers, enabling CAR-Ms to synergize with adaptive immunity by cross-priming T cells. Preclinical models highlight CAR-M efficacy in depleting immunosuppressive tumor-associated macrophages (TAMs) and reversing TME-driven immune evasion. Emerging CAR- Gamma-Delta T (CAR-γδ T) cell therapies combine CAR-mediated antigen specificity with the intrinsic tumoricidal activity of γδ T cells, which recognize stress-induced ligands independently of major histocompatibility complex (MHC) presentation. This dual-targeting capability enhances tumor selectivity while reducing on-target/off-tumor toxicity. This review systematically examines cellular sources, mechanistic advantages and clinical progress. By evaluating these platforms’ complementary strengths, we propose rational strategies for integrating CAR-NK, CAR-M, and CAR-γδ T cells into tailored therapeutic regimens for solid tumors.

Distinct Immunological Landscapes Characterize Inherited and Sporadic Mismatch Repair Deficient Endometrial Cancer

Around 30% of endometrial cancers (EC) are mismatch repair (MMR) deficient, mostly as a consequence of mutations acquired during tumorigenesis, but a significant minority is caused by Lynch syndrome (LS). This inherited cancer predisposition syndrome primes an anti-cancer immune response, even in healthy carriers. We sought to explore the intra-tumoral immunological differences between genetically confirmed LS-associated MMR-deficient (MMRd), sporadic MMR-deficient, and MMR-proficient (MMRp) EC. Endometrial tumors from women with known LS were identified (

Neutrophil extracellular traps in diseases of the female reproductive organs

Neutrophil extracellular traps (NETs) are physiologically released in response to pathogens, serving as a defense mechanism. However, excessive NET production has been implicated in various pathological conditions, including diseases of the female reproductive system. Recent studies highlight the significant role of neutrophils and NETs in cancer pathogenesis. Overproduction of NETs creates sites for tumor cell adhesion, promoting tumor cell proliferation, immune escape, and tumor progression. NET formation is associated with many diseases, including cancers of the female reproductive organs. Detection of NETs can be used as a prognostic tool for patients with diseases characterized by higher rates of NETs formation, such as cancer. In order to use NETs in diagnosis, it is possible to determine them directly or to determine NET components: extracellular DNA, citrullinated histones, NE or MPO. This review explores the role of neutrophils and NETs in the pathogenesis, diagnosis and treatment of breast, ovarian, cervical and endometrial cancer, premature lapse of ovarian function, cervicitis, endometriosis, pregnancy and pregnancy-related diseases.

Dissecting the dual role of OTU family proteins in tumor progression and immune escape

As a core mechanism regulating intracellular protein homeostasis, the dynamic equilibrium between ubiquitination and deubiquitination profoundly impacts the functionality and fate of target proteins. The Ovarian tumor domain (OTU) family, a vital subclass of deubiquitinating enzymes, comprises 16 members that mediate ubiquitin binding and hydrolysis through their characteristic OTU domain. Recent years have witnessed growing interest in OTU family members in oncology and immunology research. This review comprehensively elucidates the core mechanisms by which OTU members regulate tumor-associated signaling networks via substrate-specific deubiquitination. On one hand, they directly govern tumor cell proliferation, metastasis, and apoptosis by modulating the stability of key substrates. On the other hand, they orchestrate tumor progression through dynamic regulation of inflammatory intensity, immune response duration, and immune evasion mechanisms within the tumor microenvironment (TME), thereby constructing a multidimensional regulatory network in tumor development. These findings not only unveil the pivotal role of OTU family members in tumorigenesis and immune modulation but also establish a theoretical foundation for developing novel anti-tumor therapeutics targeting deubiquitination processes. Notably, OTUs emerge as high-potential therapeutic targets with high translational relevance for refining precision-guided tumor-immunotherapy integration strategies.

Targeting ferroptosis: a promising avenue for ovarian cancer treatment

Ovarian cancer(OC) is the second most common gynecological malignancy worldwide. While traditional treatments such as cytoreductive surgery, chemotherapy, and targeted drugs have made progress, patients with advanced disease still face high recurrence rates and resistance to treatment. As a result, there is an urgent need to develop new therapeutic strategies. Ferroptosis, a novel form of programmed cell death characterized by iron-dependent lipid peroxidation, has recently gained attention for its potential in cancer therapy. Studies indicate that OC cells are highly sensitive to ferroptosis, and targeting this pathway can effectively overcome chemotherapy resistance and improve treatment outcomes. This review systematically examines the molecular mechanisms of ferroptosis and its role in OC, with a focus on its involvement in tumor initiation, progression, TME and resistance. Furthermore, we highlight the research advancements on various ferroptosis inducers, including natural products, small molecule compounds, and nanotechnology, and explore their potential in overcoming resistance and enhancing patient prognosis. We also discuss the challenges facing ferroptosis-based treatments for OC, such as species differences, drug resistance, personalized treatment needs, and clinical translation issues. Ultimately, targeted modulation of ferroptosis offers new hope for OC therapy. Future research should focus on further elucidating its molecular mechanisms and exploring effective inducers and combination therapies to enhance its clinical applicability in precision and personalized medicine.

Exercise-downregulated CD300E acted as a negative prognostic implication and tumor-promoted role in pan-cancer

BackgroundBreast cancer ranks as one of the most prevalent malignancies among women globally, with increasing incidence rates. Physical activity, particularly exercise, has emerged as a potentially significant modifier of cancer prognosis, influencing tumor biology and patient outcomes.MethodsUsing a murine breast cancer model, we established a control and an exercise group, where the latter was subjected to 21 days of voluntary running. RNA Sequencing, bioinformatics analysis, pan-cancer analysis, and cell experiments were performed to validate the underlying mechanisms.ResultsWe observed that exercise significantly reduced tumor size and weight, without notable changes in body weight, suggesting that physical activity can modulate tumor dynamics. mRNA sequencing post-exercise revealed substantial downregulation of CD300E in the exercise group, accompanied by alterations in critical pathways such as MicroRNAs in cancers and the Calcium signaling pathway. Expanding our analysis to a broader cancer spectrum, CD300E demonstrated significant expression variability across multiple cancer types, with pronounced upregulation in myeloma, ovarian, lung, and colorectal cancers. This upregulation was correlated with poorer prognostic outcomes, emphasizing CD300E’s potential role as a prognostic marker and therapeutic target. Moreover, CD300E expression was associated with cancer cell proliferation and apoptosis.ConclusionThe study highlights the dual role of exercise in modulating gene expression relevant to tumor growth and the potential of CD300E as a target in cancer therapeutics. Further research is encouraged to explore the mechanisms by which exercise and CD300E influence cancer progression and to develop targeted strategies that could enhance patient outcomes in clinical settings.

New immune phenotypes for treatment response in high-grade serous ovarian carcinoma patients

Despite advances in surgical and therapeutic approaches, high-grade serous ovarian carcinoma (HGSOC) prognosis remains poor. Surgery is an indispensable component of therapeutic protocols, as removal of all visible tumor lesions (cytoreduction) profoundly improves the overall survival. Enhanced predictive tools for assessing cytoreduction are essential to optimize therapeutic precision. Patients’ immune status broadly reflects the tumor cell biological behavior and the patient responses to disease and treatment. Serum cytokine profiling is a sensitive measure of immune adaption and deviation, yet its integration into treatment paradigms is underexplored. This study is part of the IMPACT trial (NCT03378297) and aimed to characterize immune responses before and during primary treatment for HGSOC to identify biomarkers for treatment selection and prognosis. Longitudinal serum samples from 22 patients were collected from diagnosis until response evaluation. Patients underwent primary cytoreductive surgery or neoadjuvant chemotherapy (NACT) based on laparoscopy scoring. Twenty-seven serum cytokines analyzed by Bio-Plex 200, revealed two immune phenotypes at diagnosis: Immune High with marked higher serum cytokine levels than Immune Low. The immune phenotypes reflected the laparoscopy scoring and allocation to surgical treatment. The five Immune High patients undergoing primary cytoreductive surgery exhibited immune mobilization and extended progression-free survival, compared to the Immune Low patients undergoing the same treatment. Both laparoscopy and cytoreductive surgery induced substantial and transient changes in serum cytokines, with upregulation of the inflammatory cytokine IL-6 and downregulation of the multifunctional cytokines IP-10, Eotaxin, IL-4, and IL-7. Over the study period, cytokine levels uniformly decreased in all patients, leading to the elimination of the initial immune phenotypes regardless of treatment choice. This study reveals distinct pre-treatment immune phenotypes in HGSOC patients that might be informative for treatment stratification and prognosis. This potential novel biomarker holds promise as a foundation for improved assessment of treatment responses in patients with HGSOC. ClinicalTrials.gov Identifier: NCT03378297.

Integrated bioinformatics combined with machine learning to analyze shared biomarkers and pathways in psoriasis and cervical squamous cell carcinoma

BackgroundPsoriasis extends beyond its dermatological inflammatory manifestations, encompassing systemic inflammation. Existing studies have indicated a potential risk of cervical cancer among patients with psoriasis, suggesting a potential mechanism of co-morbidity. This study aims to explore the key genes, pathways, and immune cells that may link psoriasis and cervical squamous cell carcinoma (CESC).MethodsThe cervical squamous cell carcinoma dataset (GSE63514) was downloaded from the Gene Expression Omnibus (GEO). Two psoriasis-related datasets (GSE13355 and GSE14905) were merged into one comprehensive dataset after removing batch effects. Differentially expressed genes were identified using Limma and co-expression network analysis (WGCNA), and machine learning random forest algorithm (RF) was used to screen the hub genes. We analyzed relevant gene enrichment pathways using GO and KEGG, and immune cell infiltration in psoriasis and CESC samples using CIBERSORT. The miRNA-mRNA and TFs-mRNA regulatory networks were then constructed using Cytoscape, and the biomarkers for psoriasis and CESC were determined. Potential drug targets were obtained from the cMAP database, and biomarker expression levels in hela and psoriatic cell models were quantified by RT-qPCR.ResultsIn this study, we identified 27 key genes associated with psoriasis and cervical squamous cell carcinoma. NCAPH, UHRF1, CDCA2, CENPN and MELK were identified as hub genes using the Random Forest machine learning algorithm. Chromosome mitotic region segregation, nucleotide binding and DNA methylation are the major enrichment pathways for common DEGs in the mitotic cell cycle. Then we analyzed immune cell infiltration in psoriasis and cervical squamous cell carcinoma samples using CIBERSORT. Meanwhile, we used the cMAP database to identify ten small molecule compounds that interact with the central gene as drug candidates for treatment. By analyzing miRNA-mRNA and TFs-mRNA regulatory networks, we identified three miRNAs and nine transcription factors closely associated with five key genes and validated their expression in external validation datasets and clinical samples. Finally, we examined the diagnostic effects with ROC curves, and performed experimental validation in hela and psoriatic cell models.ConclusionsWe identified five biomarkers, NCAPH, UHRF1, CDCA2, CENPN, and MELK, which may play important roles in the common pathogenesis of psoriasis and cervical squamous cell carcinoma, furthermore predict potential therapeutic agents. These findings open up new perspectives for the diagnosis and treatment of psoriasis and squamous cell carcinoma of the cervix.

Fatty acid transport protein inhibition sensitizes breast and ovarian cancers to oncolytic virus therapy via lipid modulation of the tumor microenvironment

IntroductionAdipocytes in the tumour microenvironment are highly dynamic cells that have an established role in tumour progression, but their impact on anti-cancer therapy resistance is becoming increasingly difficult to overlook.MethodsWe investigated the role of adipose tissue and adipocytes in response to oncolytic virus (OV) therapy in adipose-rich tumours such as breast and ovarian neoplasms.ResultsWe show that secreted products in adipocyte-conditioned medium significantly impairs productive virus infection and OV-driven cell death. This effect was not due to the direct neutralization of virions or inhibition of OV entry into host cells. Instead, further investigation of adipocyte secreted factors demonstrated that adipocyte-mediated OV resistance is primarily a lipid-driven phenomenon. When lipid moieties are depleted from the adipocyte-conditioned medium, cancer cells are re-sensitized to OV-mediated destruction. We further demonstrated that blocking fatty acid uptake by cancer cells, in a combinatorial strategy with virotherapy, has clinical translational potential to overcome adipocyte-mediated OV resistance.DiscussionOur findings indicate that while adipocyte secreted factors can impede OV infection, the impairment of OV treatment efficacy can be overcome by modulating lipid flux in the tumour milieu.

Exploring genetic associations of Crohn’s disease and ulcerative colitis with extraintestinal cancers in European and East Asian populations

BackgroundPrevious studies have reported associations of Crohn’s disease (CD) and ulcerative colitis (UC) with the risks of extraintestinal cancers, but the causality remains unclear.MethodsUsing genetic variations robustly associated with CD and UC extracted from genome-wide association studies (GWAS) as instrumental variables. Nine types of extraintestinal cancers of European and Asian populations were selected as outcomes. We used the inverse variance weighted method as the primary approach for two-sample Mendelian randomization analysis. Sensitivity analyses were carried out to evaluate the reliability of our findings.ResultsIn the European population, we found that CD showed a potential causal relationship with pancreatic cancer (OR: 1.1042; 95% CI: 1.0087-1.2088; P=0.0318). Meanwhile, both CD (outliers excluded: OR: 1.0208; 95% CI: 1.0079-1.0339; P=0.0015) and UC (outliers excluded: OR: 1.0220; 95% CI: 1.0051-1.0393; P=0.0108) were associated with a slight increase in breast cancer risk. Additionally, UC exhibited a potential causal effect on cervical cancer (outliers excluded: OR: 1.1091; 95% CI: 1.0286-1.1960; P=0.0071). In the East Asian population, CD had significant causal effects on pancreatic cancer (OR: 1.1876; 95% CI: 1.0741-1.3132; P=0.0008) and breast cancer (outliers excluded: OR: 0.9452; 95% CI: 0.9096-0.9822; P=0.0040). For UC, it exhibited significant causal associations with gastric cancer (OR: 1.1240; 95% CI: 1.0624-1.1891; P=4.7359×10–5), bile duct cancer (OR: 1.3107; 95% CI: 1.0983-1.5641; P=0.0027), hepatocellular carcinoma (OR: 1.2365; 95% CI: 1.1235-1.3608; P=1.4007×10–5) and cervical cancer (OR: 1.3941; 95% CI: 1.1708-1.6599; P=0.0002), as well as a potential causal effect on lung cancer (outliers excluded: OR: 1.1313; 95% CI: 1.0280-1.2449; P=0.0116).ConclusionsOur study provided evidence that genetically predicted CD may be a risk factor for pancreatic and breast cancers in the European population, and for pancreatic cancer in the East Asian population. Regarding UC, it may be a risk factor for cervical and breast cancers in Europeans, and for gastric, bile duct, hepatocellular, lung, and cervical cancers in East Asians. Therefore, patients with CD and UC need to emphasize screening and prevention of site-specific extraintestinal cancers.

The overexpression of actin related protein 2/3 complex subunit 1B(ARPC1B) promotes the ovarian cancer progression via activation of the Wnt/β-catenin signaling pathway

IntroductionOvarian cancer is one of the most fatal malignancies of the female reproductive system. The purpose of this study is to explore the mechanism of Actin Related Protein 2/3 Complex Subunit 1B(ARPC1B) in the progression of ovarian cancer.MethodsThe expressions and prognostic value of ARPC1B in ovarian cancer were identified using the GEPIA database and the Kaplan-Meier Plotter database. The expression of ARPC1B was manipulated to evaluate its impact on the malignant phenotypes of ovarian cancer. The cell proliferation ability was analyzed through CCK-8 assay and clone formation assay. The cell migration and invasion capacity was evaluated through wound healing assay and trans well assay. Mice xenografts were conducted to measure the effects of ARPC1B on tumor development in vivo.ResultsOur data suggested that ARPC1B was overexpressed in ovarian cancer, which was correlated with a poorer survival compared to low mRNA expression of ARPC1B in ovarian cancer patients. The overexpression of ARPC1B promoted cell proliferation, migration, and invasion of ovarian cancer cells. Conversely, the knockdown of ARPC1B resulted in the opposite effect. Additionally, ARPC1B expression could activate Wnt/β-catenin signaling pathway. The administration of the β-catenin inhibitor XAV-939 abolished the promotion of cell proliferation, migration, and invasion activities induced by ARPC1B overexpression in vitro.ConclusionsARPC1B was overexpressed in ovarian cancer and was correlated with poor prognosis. ARPC1B promoted ovarian cancer progression through activation of Wnt/β-catenin Signaling Pathway.

Increased levels of NETosis biomarkers in high-grade serous ovarian cancer patients’ biofluids: Potential role in disease diagnosis and management

IntroductionHigh-grade serous ovarian cancer (HGSOC) is the second most frequent gynecological malignancy but the most lethal, partially due to the spread of the disease through the peritoneal cavity. Recent evidence has shown that, apart from their role in immune defense through phagocytosis and degranulation, neutrophils are able to participate in cancer progression through the release of neutrophil extracellular traps (NETs) in a process called NETosis. NETs are composed of DNA, histones, calprotectin, myeloperoxidase (MPO) and elastase and the NETosis process has been proposed as a pre-requisite for the establishment of omental metastases in early stages of HGSOC. Nevertheless, its role in advanced stages remains to be elucidated. Therefore, our principal aim is to characterize a NETosis biomarker profile in biofluids from patients with advanced HGSOC and control women. MethodsSpecifically, five biomarkers of NETosis (cell-free DNA (cfDNA), nucleosomes, citrullinated histone 3 (citH3), calprotectin and MPO) were quantified in plasma and peritoneal fluid (PF) samples from patients (n=45) and control women (n=40).ResultsOur results showed that HGSOC patients presented a higher concentration of cfDNA, citH3 and calprotectin in plasma and of all five NETosis biomarkers in PF than control women. Moreover, these biomarkers showed a strong ability to differentiate the two clinical groups. Interestingly, neoadjuvant treatment (NT) seemed to reduce NETosis biomarkers mainly systemically (plasma) compared to the tumor environment (PF).DiscussionIn conclusion, NETosis biomarkers are present in the tumor environment of patients with advanced HGSOC, which might contribute to the progression of the disease. Besides, plasma cfDNA and calprotectin could represent minimally invasive surrogate biomarkers for HGSOC. Finally, NT modifies NETosis biomarkers levels mainly at the systemic level.

APOs as promising prognostic biomarkers: correlation with tumor-infiltrating leukocytes in endometrial cancer

Background Apolipoproteins (APOs) are essentially structural and functional components of lipoproteins, which are composed of 22 members and their effects on certain types of cancer have been studied. However, their roles in endometrial cancer (EC), which is one of the most common malignant tumors in gynecology were unclear and rarely investigated. Methods We investigated the expression levels of APOs genes in EC. Furthermore, we explored the roles of APOs in prognostic value, and immune infiltrates in EC patients by using different bioinformatics databases. In-vitro experiments were also conducted to evaluate the effect of APOs genes expression on migrant abilities of EC cells. Results Nine APO genes (APOC1, APOC2, APOC4, APOD, APOE, APOL3, APOL4, APOLD1, and APOO) were found differently expressed between EC and control tissues by the GEPIA2. However, APOC4 was not included in the subsequent analysis due to its low expression in EC tissues. Moreover, mRNA expression levels of APOs were found correlated with the clinicopathological characteristics of EC, including stage, grade, molecular subgroups, p53 mutant conditions, PTEN mutant conditions, and expression levels of ESR1 and ESR2. Meanwhile higher expression levels of APOs were significantly correlated with better (APOD, APOL3) or poorer (APOC1, APOE, APOLD1) OS. ssGSEA showed 7 TILs in EC which differed significantly from those in adjacent noncancerous tissues were correlated with prognosis of EC patients. The expression levels of both APOD and APOE were positively correlated with all 7 TILs. Finally, western blotting showed that 17β-estradiol (E2) increased APOE protein expression level and reduced APOD protein expression level. Furthermore, APOE was identified to promote the cell migration by scratch assay. Conclusion The expression of APOs may be a promising prognostic biomarker and is associated with immune invasion as a potential target for endometrial cancer.

A cyclic peptide-based PROTAC induces intracellular degradation of palmitoyltransferase and potently decreases PD-L1 expression in human cervical cancer cells

IntroductionOur previous research has found that degradation of palmitoyltransferase in tumor cells using a linear peptide PROTAC leads to a significant decrease in PD-L1 expression in tumors. However, this degradation is not a sustained and efficient process. Therefore, we designed a cyclic peptide PROTAC to achieve this efficient anti-PD-L1 effect.MethodsWe designed and synthesized an improvement in linear peptide PROTAC targeting palmitoyltransferase DHHC3, and used disulfide bonds to stabilize the continuous N- and C-termini of the peptides to maintain their structure. Cellular and molecular biology techniques were used to test the effect of this cyclic peptide on PD-L1.ResultsIn human cervical cancer cells, our cyclic peptide PROTAC can significantly downregulate palmitoyl transferase DHHC3 and PD-L1 expressions. This targeted degradation effect is enhanced with increasing doses and treatment duration, with a DC50 value much lower than that of linear peptides. Additionally, flow cytometry analysis of fluorescence intensity shows an increase in the amount of cyclic peptide entering the cell membrane with prolonged treatment time and higher concentrations. The Cellular Thermal Shift Assay (CETSA) method used in this study indicates effective binding between our novel cyclic peptide and DHHC3 protein, leading to a change in the thermal stability of the latter. The degradation of PD-L1 can be effectively blocked by the proteasome inhibitor MG132. Results from clone formation experiments illustrate that our cyclic peptide can enhance the proliferative inhibition effect of cisplatin on the C33A cell line. Furthermore, in the T cell-C33A co-culture system, cyclic peptides target the degradation of PD-L1, thereby blocking the interaction between PD-L1 and PD-1, and promoting the secretion of IFN-γ and TNF-α in the co-culture system supernatant.ConclusionOur results demonstrate that a disulfide-bridged cyclic peptide PROTAC targeting palmitoyltransferase can provide a stable and improved anti-PD-L1 activity in human tumor cells.

The bispecific antibody targeting VISTA and PD-L1 shows enhanced tumor inhibitory activity in pancreatic, endometrial and breast cancers compared to mono- and combination immune checkpoint blockade

BackgroundThe introduction of checkpoint immunotherapeutic agents in the last decade has revolutionized cancer treatment. Although anti-PD-1, anti-PD-L1 and anti-CTLA4 are promising therapies, many patients fail to respond or relapse due to drug resistance potentially due to redundancy of immune checkpoints. One of the ways to improve the efficacy of this cancer treatment is to target two or even three immune checkpoints. To date, the benefit of combined anti-VISTA/anti-PD-L1 therapy has been confirmed, but no one has investigated the efficacy of blocking these negative immune checkpoints with a bispecific anti-VISTA/anti-PD-L1 antibody.MethodsIn this study, the bispecific antibodies (bsAbs) were produced in three formats: symmetric (IgG-HC-scFv), asymmetric (Fab-scFv-Fc(KIH)) and 2 x scFv. The binding and blocking properties of these bispecific antibodies (bsAbs) and their efficacy compared to monotherapy and combination therapy were then determined using endometrial (RL95-2), pancreatic (PANC-1) and breast (BT-20) cancer cell lines.ResultsThe bsAbs generated in this study showed weaker binding properties to PD-1 and VISTA in ELISA (EC50) than the parent antibodies (atezolizumab and onvatilimab). Blockade of VISTA/VSIG-3 binding was also weaker with bsAbs compared to onvatilimab, but the ability to block the PD-1/PD-L1 pathway was slightly better than with atezolizumab. The Fc-based bsAbs showed statistically significant higher levels of lysis of endometrial, breast and pancreatic cancer cells. The symmetric bsAbs (IgG-HC-scFv) showed the most promising therapeutic potential. Higher levels of cancer cell lysis were associated with higher levels of pro-inflammatory cytokines. Both the asymmetric and symmetric bsAbs resulted in higher secretion levels of IFN-γ, TNFα and Granzyme B than anti-VISTA, anti-PD-L1 monotherapy and anti-VISTA/anti-PD-L1 combination therapy.ConclusionThe high level of tumor cell lysis and increased expression of pro-inflammatory cytokines induced by the Fc-based bsAbs suggest a novel approach for the treatment of pancreatic, endometrial and breast cancer.

Role of TIM-3 in ovarian cancer: the forsaken cop or a new noble

T cell immunoglobulin and mucin domain-3 (TIM-3), a crucial immune checkpoint following PD1 and CTLA4, is widely found in several immune cells. Nonetheless, its performance in recent clinical trials appears disappointing. Ovarian cancer (OC), a malignant tumor with a high mortality rate in gynecology, faces significant hurdles in immunotherapy. The broad presence of TIM-3 offers a new opportunity for immunotherapy in OC. This study reviews the role of TIM-3 in OC and assesses its potential as a target for immunotherapy. The regulatory effects of TIM-3 on the immune microenvironment in OC are discussed, with a focus on preclinical studies that demonstrate TIM-3’s modulation of various immune cells in OC. Additionally, the potential therapeutic advantages and challenges of targeting TIM-3 in OC are examined.

Identification of telomere-related lncRNAs and immunological analysis in ovarian cancer

BackgroundOvarian cancer (OC) is a global malignancy characterized by metastatic invasiveness and recurrence. Long non-coding RNAs (lncRNAs) and Telomeres are closely connected with several cancers, but their potential as practical prognostic markers in OC is less well-defined.MethodsRelevant mRNA and clinical data for OC were sourced from The Cancer Genome Atlas (TCGA) database. The telomere-related lncRNAs (TRLs) prognostic model was established by univariate/LASSO/multivariate regression analyses. The effectiveness of the TRLs model was evaluated and measured via the nomogram. Additionally, immune infiltration, tumor mutational load (TMB), and drug sensitivity were evaluated. We validated the expression levels of prognostic genes. Subsequently, PTPRD-AS1 knockdown was utilized to perform the CCK8 assay, colony formation assay, transwell assay, and wound healing assay of CAOV3 cells.ResultsA six-TRLs prognostic model (PTPRD-AS1, SPAG5-AS1, CHRM3-AS2, AC074286.1, FAM27E3, and AC018647.3) was established, which can effectively predict patient survival rates and was successfully validated using external datasets. According to the nomogram, the model could effectively predict prognosis. Furthermore, we detected the levels of regulatory T cells and M2 macrophages were comparatively higher in the high-risk TRLs group, but the levels of activated CD8 T cells and monocytes were the opposite. Finally, the low-risk group was more sensitive to anti-cancer drugs. The mRNA levels of PTPRD-AS1, SPAG5-AS1, FAM27E3, and AC018647.3 were significantly over-expressed in OC cell lines (SKOV3, A2780, CAOV3) in comparison to normal IOSE-80 cells. AC074286.1 were over-expressed in A2780 and CAOV3 cells and CHRM3-AS2 only in A2780 cells. PTPRD-AS1 knockdown decreased the proliferation, cloning, and migration of CAOV3 cells.ConclusionOur study identified potential biomarkers for the six-TRLs model related to the prognosis of OC.

Immune-related adverse events and neutrophil-to-lymphocyte ratio as prognostic indicators in gynecologic cancer patients receiving pembrolizumab: a real-world analysis

Objective To investigate whether immune-related adverse events and pretreatment neutrophil-to-lymphocyte ratio can serve as predictive biomarkers of treatment response and survival in patients with gynecologic cancer receiving pembrolizumab immunotherapy. Methods This retrospective study included 94 patients with gynecologic malignancies treated with pembrolizumab at Kaohsiung Chang Gung Memorial Hospital between May 2017 and July 2024. Detailed clinical and laboratory data including the occurrence of immune-related adverse events, pretreatment neutrophil-to-lymphocyte ratio, mismatch repair (MMR) status, treatment response patterns, and patient demographics were collected. Progression-free survival and overall survival were analyzed using Kaplan-Meier curves and Cox regression models. The optimal neutrophil-to-lymphocyte ratio cut-off value for predicting the prognosis was determined using receiver operating characteristic curve analysis. Results Overall, immune-related adverse events occurred in 55.3% of the patients and were associated with a significantly higher objective response rate (ORR; 84.6% vs. 15.4%, p < 0.001), longer progression-free survival ( p < 0.001), and improved overall survival ( p < 0.001). Similarly, low neutrophil-to-lymphocyte ratio (<4.07) also predicted longer progression-free survival (HR: 0.537, p = 0.043) and improved overall survival (HR: 0.328, p = 0.001). Multivariate analysis confirmed that both immune-related adverse events and low neutrophil-to-lymphocyte ratio were robust independent predictors of progression-free survival and overall survival. MMR-deficient tumors were associated with a significantly higher ORR (60.9% vs. 28.9%, p = 0.011), although MMR status was not independently associated with survival in the final multivariate models. Conclusion The development of immune-related adverse events and low pretreatment neutrophil-to-lymphocyte ratio independently predicted improved therapeutic response and prolonged survival in gynecologic cancer patients treated with pembrolizumab. Their integration with tumor molecular profiling may optimize monitoring frequency, adjust supportive care measures, and consider treatment modifications based on individual patient risk profiles, thereby enhancing the delivery of immunotherapy in gynecologic cancers without limiting treatment access.

Big data analysis and machine learning of the role of cuproptosis-related long non-coding RNAs (CuLncs) in the prognosis and immune landscape of ovarian cancer

BackgroundOvarian cancer (OC) is a severe malignant tumor with a significant threat to women’s health, characterized by a high mortality rate and poor prognosis despite conventional treatments such as cytoreductive surgery and platinum-based chemotherapy. Cuproptosis, a novel form of cell death triggered by copper ion accumulation, has shown potential in cancer therapy, particularly through the involvement of CuLncs. This study aims to identify risk signatures associated with CuLncs in OC, construct a prognostic model, and explore potential therapeutic drugs and the impact of CuLncs on OC cell behavior.MethodsWe analyzed ovarian cancer data (TCGA-OV) from the TCGA database, including transcriptomic and clinical data from 376 patients. Using Pearson correlation and LASSO regression, we identified 8 prognostic CuLncs to construct a risk signature model. Patients were categorized into high- and low-risk groups based on their risk scores. We performed survival analysis, model validation, drug sensitivity analysis, and in vitro experiments to assess the model’s performance and the functional impact of key CuLncs on OC cell proliferation, invasion, and migration.ResultsThe prognostic model demonstrated significant predictive power, with an area under the curve (AUC) of 0.702 for 1-year, 0.640 for 3-year, and 0.618 for 5-year survival, outperforming clinical pathological features such as stage and grade. High-risk OC patients exhibited higher Tumor Immune Dysfunction and Exclusion (TIDE) scores, indicating stronger immune evasion ability. Drugs such as JQ12, PD-0325901, and sorafenib showed reduced IC50 values in the high-risk group, suggesting potential therapeutic benefits. In vitro experiments revealed that knockdown of LINC01956, a key CuLnc in the risk signature, significantly inhibited the proliferation, invasion, and migration of OC cells (P<0.05).ConclusionOur study identified a prognostic risk model based on CuLncs and explored their potential as therapeutic targets in OC. The findings highlight the importance of CuLncs in OC prognosis and immune response, providing new insights for future research and clinical applications.

Preliminary Safety and Potential Effect of 6B11-OCIK Adoptive Cell Therapy Against Platinum-Resistant Recurrent or Refractory Ovarian Cancer

Ovarian cancer is a leading cause of death among gynecological malignancies, and novel therapies are urgently needed. Here we report preliminary findings on the potential safety and efficacy of 6B11-OCIK, an adoptive cell therapy of autologous T cells induced by the humanized anti-idiotypic antibody 6B11 minibody plus dendritic cells and cytokines, against platinum-resistant recurrent or refractory ovarian cancer in three patients. We found that 6B11-OCIK treatment was safe and well tolerated after five cycles of intravenous infusion with an initial dose of 1–2×109 cells and a dose-climbing strategy. Hemoglobin, platelets, white cell count, creatinine or liver enzyme values, coagulation function, kidney and heart function were not significantly affected over the duration of therapy. Two of the three enrolled patients showed potentially drug-related grade 1 and 2 weakness, and no other adverse events were observed. Of the three enrolled patients, one had stable disease and two showed disease progression. The patient with favorable clinical efficacy had better immune response as measured by 6B11-OCIK proliferation capacity, activation ability of CD3+CD8+ tumor-specific cytotoxic T lymphocytes and CD3+CD56+ cytokine-induced killer cells, and tumor cell killing efficiency. Changes in circulating tumor cells after treatment were consistent with serum level CA125 in the patient with stable disease (both decreased), while differences were observed in the two patients with disease progression (increased CA125 in both and decreased CTC in the patient with better immune response), suggesting that variation of circulating tumor cells was more consistent with immune response and reflected efficacy directly. This preliminary study suggested that autologous 6B11-OCIK treatment was safe and had potential clinical efficacy against ovarian cancer. Patients with better immune response had more favorable efficacy. In addition to imaging, CA125 and immunophenotypes, CTC monitoring may represent a potential indicator of immunotherapy response.

Targeted drug delivery system for ovarian cancer microenvironment: Improving the effects of immunotherapy

Immunotherapies have shown modest benefits in the current clinical trials for ovarian cancer. The tumor microenvironment (TME) in an immunosuppressive phenotype contributes to this “failure” of immunotherapy in ovarian cancer. Many stromal cell types in the TME (e.g., tumor-associated macrophages and fibroblasts) have been identified as having plasticity in pro- and antitumor activities and are responsible for suppressing the antitumor immune response. Thus, the TME is an extremely valuable target for adjuvant interventions to improve the effects of immunotherapy. The current strategies targeting the TME include: 1) eliminating immunosuppressive cells or transforming them into immunostimulatory phenotypes and 2) inhibiting their immunosuppressive or pro-tumor production. Most of the effective agents used in the above strategies are genetic materials (e.g., cDNA, mRNA, or miRNA), proteins, or other small molecules (e.g., peptides), which are limited in their target and instability. Various formulations of drug delivery system (DDS) have been designed to realize the controlled release and targeting delivery of these agents to the tumor sites. Nanoparticles and liposomes are the most frequently exploited materials. Based on current evidence from preclinical and clinical studies, the future of the DDS is promising in cancer immunotherapy since the combination of agents with a DDS has shown increased efficacy and decreased toxicities compared with free agents. In the future, more efforts are needed to further identify the hallmarks and biomarkers in the ovarian TME, which is crucial for the development of more effective, safe, and personalized DDSs.

Efficacy evaluation of multi-immunotherapy in ovarian cancer: From bench to bed

Ovarian cancer, one of the most common gynecological malignancies, is characterized by high mortality and poor prognosis. Cytoreductive surgery and chemotherapy remain the mainstay of ovarian cancer treatment, and most women experience recurrence after standard care therapies. There is compelling evidence that ovarian cancer is an immunogenic tumor. For example, the accumulation of tumor-infiltrating lymphocytes is associated with increased survival, while increases in immunosuppressive regulatory T cells are correlated with poor clinical outcomes. Therefore, immunotherapies targeting components of the tumor microenvironment have been gradually integrated into the existing treatment options, including immune checkpoint blockade, adoptive cell therapy, and cancer vaccines. Immunotherapies have changed guidelines for maintenance treatment and established a new paradigm in ovarian cancer treatment. Despite single immunotherapies targeting DNA repair mechanisms, immune checkpoints, and angiogenesis bringing inspiring efficacy, only a subset of patients can benefit much from it. Thus, the multi-immunotherapy investigation remains an active area for ovarian cancer treatment. The current review provides an overview of various clinically oriented forms of multi-immunotherapy and explores potentially effective combinational therapies for ovarian cancer.

A durable response to programmed cell death 1 blockade in a multidrug-resistant recurrent ovarian cancer patient with HLA-B44 supertype: A case report

Relapsed/refractory ovarian cancer, especially platinum resistance recurrence, remains a major therapeutic challenge. Here, we present the case of a patient with recurrent ovarian clear cell carcinoma (OCCC) who failed to respond to multiline chemotherapy and target therapy but achieved an immune complete response (iCR) with programmed cell death 1 (PD-1) inhibitor treatment. The overall survival (OS) was 59 months, and the recurrence-free survival (RFS) was 34 months after immunotherapy, which was counting. Meantime, molecular testing results revealed that traditional biomarkers for immunotherapy, including PD-L1 expression, microsatellite instability (MSI), and tumor mutational burden (TMB), were negative. HLA-B44 (B*18:01) supertype was confirmed by sequence-based HLA typing. This case raises the possibility that ovarian cancer patients with multidrug resistance may still benefit from PD-1 inhibitor therapy, even if PD-L1 pathology is negative.

Elevated Galectin-3 levels in the tumor microenvironment of ovarian cancer – implication of ROS mediated suppression of NK cell antitumor response via tumor-associated neutrophils

IntroductionOvarian cancer is a lethal disease with low survival rates for women diagnosed in advanced stages. Current cancer immunotherapies are not efficient in ovarian cancer, and there is therefore a significant need for novel treatment options. The β-galactoside-binding lectin, Galectin-3, is involved in different immune processes and has been associated with poor outcome in various cancer diagnoses. Here, we investigated how Galectin-3 affects the interaction between natural killer (NK) cells and neutrophils in the tumor microenvironment of ovarian cancer.MethodAscites from the metastatic tumor microenvironment and cyst fluid from the primary tumor site were collected from patients with high-grade serous carcinoma (HGSC) together with peripheral blood samples. Galectin-3 concentration was measured in ascites, cyst fluid and serum or plasma. Neutrophils isolated from HGSC ascites and autologous blood were analyzed to evaluate priming status and production of reactive oxygen species. In vitro co-culture assays with NK cells, neutrophils and K562 target cells (cancer cell line) were conducted to evaluate NK cell viability, degranulation and cytotoxicity.ResultsHigh levels of Galectin-3 were observed in cyst fluid and ascites from patients with HGSC. Neutrophils present in HGSC ascites showed signs of priming; however, the priming status varied greatly among the patient samples. Galectin-3 induced production of reactive oxygen species in ascites neutrophils, but only from a fraction of the patient samples, which is in line with the heterogenous priming status of the ascites neutrophils. In co-cultures with NK cells and K562 target cells, we observed that Galectin-3-induced production of reactive oxygen species in neutrophils resulted in decreased NK cell viability and lowered anti-tumor responses.ConclusionTaken together, our results demonstrate high levels of Galectin-3 in the tumormicroenvironment of HGSC. High levels of Galectin-3 may induce production of reactiveoxygen species in ascites neutrophils in some patients. In turn, reactive oxygen species produced by neutrophils may modulate the NK cell anti-tumor immunity. Together, this study suggests further investigation to evaluate if a Galectin-3-targeting therapy may be used in ovarian cancer.

The promise of PD1/PDL1 targeted immunotherapy in locally advanced cervical cancer: a game-changer for patients outcome?

Locally advanced cervical cancer remains a significant therapeutic challenge, with high rates of recurrence and metastasis despite advances in chemoradiation. Immunotherapy, particularly immune checkpoint inhibitors targeting the PD-1/PD-L1 axis, has emerged as a promising strategy to enhance treatment efficacy. This review explores the integration of immunotherapy with standard chemoradiation, highlighting the potential of PD-1 inhibitors, such as pembrolizumab, in improving progression-free survival (PFS) among high-risk patients. Furthermore, the role of predictive biomarkers, including microsatellite instability (MSI) and tumor mutational burden (TMB), is examined to refine patient selection and personalize therapeutic approaches. Emerging strategies, including the use of nivolumab, ipilimumab, and maintenance immunotherapy, are also discussed. While preliminary clinical data are encouraging, further research is required to optimize treatment combinations, establish robust patient selection criteria, and enhance long-term outcomes in cervical cancer management.

Critical role of reproductive tract microbiota and derived metabolites in inflammation, tumor immunity, and tumorigenesis of gynecological cancers: a narrative review

Gynecological malignancies, including ovarian, cervical, and endometrial cancers, present significant clinical challenges due to the epidemiological complexity and limitations in current therapeutic strategies. Emerging evidence highlights the critical role of the microbiome and its metabolites in modulating tumor initiation, progression, and treatment responses. This review explores the intricate mechanisms through which gut and reproductive tract microbiota influence gynecological cancers via immune regulation, metabolic reprogramming, and epigenetic modifications. Key microbial metabolites, such as short-chain fatty acids, bile acids, and estrogen-metabolizing intermediates, serve as molecular bridges in host-microbe communication, impacting chemotherapy resistance and immunotherapy efficacy. Furthermore, we discuss the translational potential of microbiome-targeted interventions, including probiotics, fecal microbiota transplantation, and precision microbial therapies, as innovative approaches for diagnosis, prognosis, and treatment. Understanding the microbiota-reproductive axis offers novel insights into overcoming therapeutic resistance and improving patient outcomes in gynecologic oncology.

A predictive model for the transformation from cervical inflammation to cancer based on tumor immune-related factors

IntroductionPersistent high-risk human papillomavirus (HR-HPV) infection is crucial in transforming cervical intraepithelial neoplasia (CIN) into cervical cancer (CC) by evading immune responses. Additionally, changes in the tumor immune microenvironment (TIME) are increasingly linked to CIN progression to CC.MethodsIn this study, we used public databases to collect transcriptome data for CIN, CC, and normal cervix, employing LASSO regression to find TIP genes with differential expression. We also used the CIBERSORT algorithm to analyze immune cells in the cervix. ROC curves were plotted to assess tumor-infiltrating immune cells (TICs) and the expression of tumor-infiltrating cell-related genes (TICRGs) for predicting CC efficacy and identifying immune-related genes and cells associated with cervical disease progression for future modeling. We developed a cervical "inflammation-cancer transition" prediction model using the random forest algorithm and assessed its accuracy with internal and external data. Clinical samples from two hospitals were analyzed using multiplexed immunohistochemistry (mIHC) to detect risk factors in various cervical diseases, serving as an independent validation cohort for the model's reliability.ResultsFour genes, ARG2, HSP90AA1, EZH2, ICAM1, and two immune cells, M1 macrophages and activated CD4 memory T cells, were selected as variables, and a predictive model was constructed. The model achieved an AUC of 1 for internal training sets and 0.912 for testing sets. For validation cohort, the AUC was 0.864 for GSE7803 and 0.918 for TCGA/GTEx. For external validation (GSE39001, GSE149763, and GSE138080), the AUC was 0.703, 0.889 and 0.696. At the same time, the mIHC experimental results also effectively validated the stability of the model.DiscussionIn conclusion, the developed model enhances the predictive accuracy for the progression of CIN to CC and offers novel insights for the early diagnosis and screening of CC.

Both complete response and long-term survival after combination therapy with toripalimab in a patient with meta-oligometastases cervical cancer: a case report

BackgroundThe therapeutic landscape for recurrent or metastatic cervical cancer remains limited, with few options available. According to National Comprehensive Cancer Network (NCCN) guidelines, pembrolizumab combined with chemotherapy, with or without bevacizumab, is recommended for affected patients. Despite these guidelines, recurrence rates remain elevated, and survival outcomes following standard interventions are unsatisfactory. Furthermore, real-world management of recurrent or metastatic cervical cancer presents inherent complexities, often requiring an integrative, multidimensional treatment approach to enhance long-term survival. The pressing need to refine and adopt multimodal therapeutic strategies is evident in addressing the persistent challenges associated with disease recurrence and progression.Case descriptionThe case involved a 40-year-old female diagnosed with advanced cervical cancer who underwent radical hysterectomy. Postoperative pathology identified high-risk features, including lymph node involvement, necessitating adjuvant chemoradiotherapy. However, disease progression occurred during treatment, manifesting as metastases in the left supraclavicular and axillary lymph nodes. Subsequent local radiotherapy and systemic therapy led to a favorable response. By November 2024, overall survival (OS) had surpassed 72 months, with toripalimab administered for 65 months, during which no immunotherapy-related adverse events occurred.ConclusionThis case offers clinical insight into the efficacy and safety of integrating chemotherapy, immunotherapy, and radiotherapy in recurrent or metastatic cervical cancer. The multimodal approach contributes to prolonged survival in this patient. Further clinical trials are essential to substantiate the therapeutic benefits of this regimen in broader patient cohorts.

Physicochemical and biological characterization of a bispecific antibody in a CrossMab/KIH format that targets EGFR and VEGF-A

IntroductionBispecific antibodies (BsAbs) are a class of antibody therapeutics engineered in various molecular formats to bind two distinct antigens and potentially mediate multiple biological effects. These molecular formats are tailored to mediate specific mechanisms of action and possess unique physicochemical and biological properties that are necessary to assure product quality. In ovarian cancer (OC), both EGFR- and VEGF-A-mediated signaling pathways are often upregulated and cooperate to promote tumor growth and angiogenesis. Thus, inhibiting of EGFR- and VEGF-A pathways with a BsAb may provide synergistic anti-tumor activity.MethodsUsing publicly available sequences and applying immunoglobulin domain crossover (CrossMab) and knobs-into-holes (KIH) technologies, we generated a BsAb to simultaneously bind EGFR and VEGF-A (designated as anti-EGFR/VEGF-A BsAb). This BsAb served as a model for physiochemical and biological characterization of quality attributes that would be critical for the BsAb’s mechanisms of action. Our goal was to gain fundamental insights into BsAbs designed to target a receptor with one arm and a soluble ligand with the other, to support bioassay development and inform quality control strategies. ResultsOur data demonstrated that the CrossMab/KIH platform successfully produced a correctly assembled BsAb during cell culture. Characterization confirmed that the anti-EGFR/VEGF-A BsAb bound both EGFR and VEGF-A with comparable activity and affinity to the respective parental monoclonal antibodies. Functionally, the BsAb disrupted both EGF/EGFR and VEGF-A/VEGFR2 signaling pathways in OC and human umbilical vein endothelial cell (HUVEC) models. Furthermore, the BsAb effectively blocked angiogenic signaling driven by VEGF-A secreted from OC cells in a paracrine manner.DiscussionBased on the combinatorial mechanism of action and our characterization findings, we concluded that two or more bioassays may be needed to accurately assess the activity of both arms of this type of BsAb.

The heterogeneity of genomic alterations, metastatic patterns and immune microenvironment in metastatic ovarian cancer originating from colorectal cancer

PurposeThe ovarian metastases originating from colorectal cancer (CRCOM) develops rapidly and lethally. Previously, the genetic alterations and metastatic pathway in CRCOM were not well understood. The aim of this study is to explore the special molecular phenotype and dissemination patterns of CRCOM.MethodsThe whole-exome sequencing (WES) was performed on 65 matched tissue samples from 11 CRCOM patients, including 11 primary colorectal cancer (CRC) with 11 matched normal tissues, and 43 multi-site metastases (including 15 CRCOMs and 4 patients had bilateral ovarian metastases (OMs). Genetic landscape, neoantigens, tumor clonal origin and spread of CRCOMs were analyzed. TCGA-COAD dataset combined with our data were used for survival analysis and validation of the findings.ResultsThere was significant intertumoral heterogeneity among patients with CRCOM and intra-tumoral heterogeneity among multiorgan metastases. 19 genes were inferred as the potential driver genes of CRCOM. USP7 and RPA1 were HRD-related mutations and potential to serve as predictive biomarkers in OM. The putative neoantigen number of the primary CRC and OM varies widely among patients. The OM showed an immune desert state, extremely deficient in each subtype of immune cells. According to COSMIC signatures features, the CRCOM patients were divided into two groups, which are different in overall survival (OS) (median OS, 720 days vs 360 days, P = 0.074) and genetic alterations. Two metastatic patterns of CRCOM were summarized, which were primary CRC to OM, and metastases to metastases (including lymph node metastases (LNM) to OM, peritoneal metastases (PM) to OM, and other metastases to OM). Interestingly, the sources of bilateral OM might be different in the two patients.ConclusionThis study presents a better understanding the heterogeneity of the genetic characterizations and metastatic pattern in CRCOM. The subtypes of CRCOM with USP7 mutation, more copy number alterations, lower neoantigens, and immunoscore have a worse prognosis.

Tertiary lymphoid structures in ovarian cancer

Ovarian cancer (OC) is a significant cause of cancer-related mortality in women worldwide. Despite advances in treatment modalities, including surgery and chemotherapy, the overall prognosis for OC patients remains poor, particularly for patients with advanced or recurrent disease. Immunotherapy, particularly immune checkpoint blockade (ICB), has revolutionized cancer treatment in various malignancies but has shown limited efficacy in treating OC, which is primarily attributed to the immunologically. Tertiary lymphoid structures (TLSs), which are ectopic aggregates of immune cells, have emerged as potential mediators of antitumor immunity. This review explores the composition, formation, and induction of tumor associated TLS (TA-TLS) in OC, along with their role and therapeutic implications in disease development and treatment. By elucidating the roles TA-TLSs and their cellular compositions played in OC microenvironment, novel therapeutic targets may be identified to overcome immune suppression and enhance immunotherapy efficacy in ovarian cancer.

Col1A1 as a new decoder of clinical features and immune microenvironment in ovarian cancer

BackgroundsCollagen type I alpha 1 chain (COL1A1) is a key protein encoding fibrillar collagen, playing a crucial role in the tumor microenvironment (TME) due to its complex functions and close association with tumor invasiveness. This has made COL1A1 a focal point in cancer biology research. However, studies investigating the relationship between COL1A1 expression levels and clinical characteristics of ovarian cancer (OC) remain limited.MethodsThis study integrated resources from publicly available online databases and immunohistochemistry (IHC) techniques to analyze and validate COL1A1 expression in OC tissues, and evaluated its potential association with clinical features in OC patients. The prognostic value of COL1A1 was assessed using Kaplan-Meier (KM) survival curve analysis. The TIMER and TISIDB databases to explore the potential relationship between COL1A1 expression and immune microenvironment in OC tissues. The LinkedOmics and INPUT2 databases were used to analyze differential gene expression in OC, This was followed by enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) annotations to identify and predict potential signaling pathways associated with COL1A1.ResultsOur study demonstrated that COL1A1 expression was significantly elevated in OC tissues compared to normal ovarian tissues. This elevated expression was closely associated with tumor metastasis, poor prognosis, and advanced pathological stages in OC patients. Moreover, COL1A1 expression showed a significant correlation with immune cell infiltration and the expression of immune-related genes within the TME.Further analyses revealed that COL1A1 and its co-expressed genes were primarily enriched in key signaling pathways involved in OC invasion, metastasis, and angiogenesis, indicating its potential role in driving OC progression.ConclusionsOur study found that upregulation of COL1A1 expression is significantly associated with lymph node metastasis of OC and can affect the immune microenvironment. Based on this, COL1A1 could serve as a promising biomarker for OC prognosis and provide a new perspective for the development of potential immunotherapies for patients with OC.

Immunotherapy in gestational trophoblastic neoplasia: advances and future directions

Gestational trophoblastic neoplasia (GTN) is a rare but aggressive malignancy that follows normal or aberrant pregnancies. Until the advent of immunotherapy in 2017, surgery and chemotherapy were the standard treatment modalities, with chemotherapy remaining the cornerstone. However, chemoresistance and high-risk disease present significant challenges in managing GTN. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors (ICIs), have offered new hope for managing these difficult cases. This review provides the comprehensive overview of the mechanisms underlying ICIs in GTN, and explores the potential synergy of combining ICIs with targeted therapies, such as vascular endothelial growth factor and epidermal growth factor receptor inhibitors. We also provide an overview of the latest evidence on the use of ICIs in treating GTN, focusing on their effectiveness in both low- and high-risk cases, as well as in chemorefractory settings. In addition, we discuss ongoing clinical trials, immune-related adverse events associated with ICIs, biomarker-driven approaches, immunosuppressive tumor microenvironments, and the challenges posed with ICIs resistance. The review also explores future directions, including the integration of ICIs into standard regimens, the potential for personalized treatment based on tumor biology, and the importance of fertility preservation in young patients with GTN. In conclusion, while challenges remain, immunotherapy represents a promising frontier in GTN treatment, with the potential to improve outcomes and provide a more personalized approach to care

Multi-omics analysis and experiments uncover the function of cancer stemness in ovarian cancer and establish a machine learning-based model for predicting immunotherapy responses

BackgroundThe heterogeneity of cancer makes it challenging to predict its response to immunotherapy, highlighting the need to find reliable biomarkers for assessment. The sophisticated role of cancer stemness in mediating resistance to immune checkpoint inhibitors (ICIs) is still inadequately comprehended.MethodsGenome-scale CRISPR screening of RNA sequencing data from Project Achilles was utilized to pinpoint crucial genes unique to Ovarian Cancer (OV). Thirteen publicly accessible OV transcriptomic datasets, seven pan-cancer ICI transcriptomic cohorts, and one single-cell RNA dataset from melanoma patients treated with PD-1 were utilized to scale a novel cancer stemness index (CSI). An OV single-cell RNA dataset was amassed and scrutinized to uncover the role of Small Nuclear Ribonucleoprotein Polypeptide E (SNRPE) in the tumor microenvironment (TME). Vitro experiments were performed to validate the function of SNRPE in promoting proliferation and migration of ovarian cancer.ResultsThrough the analysis of extensive datasets on ovarian cancer, a specific gene set that impacts the stemness characteristics of tumors has been identified and we unveiled a negative correlation between cancer stemness, and benefits of ICI treatment in single cell ICI cohorts. This identified gene set underpinned the development of the CSI, a groundbreaking tool leveraging advanced machine learning to predict prognosis and immunotherapy responses in ovarian cancer patients. The accuracy of the CSI was further confirmed by applying PD1/PD-L1 ICI transcriptomic cohorts, with a mean AUC exceeding 0.8 for predicting tumor progression and immunotherapy benefits. Remarkably, when compared to existing immunotherapy and prognosis markers, CSI exhibited superior predictive capabilities across various datasets. Interestingly, our research unveiled that the amplification of SNRPE contribute to remodeling the TME and promoting the evasion of malignant cells from immune system recognition and SNRPE can server as a novel biomarker for predicting immunotherapy response.ConclusionsA strong relationship between cancer stemness and the response to immunotherapy has been identified in our study. This finding provides valuable insights for devising efficient strategies to address immune evasion by targeting the regulation of genes associated with cellular stemness.

Enhancing oncolytic virotherapy by extracellular vesicle mediated microRNA reprogramming of the tumour microenvironment

BackgroundThere has been limited success of cancer immunotherapies in the treatment of ovarian cancer (OvCa) to date, largely due to the immunosuppressive tumour microenvironment (TME). Tumour-associated macrophages (TAMs) are a major component of both the primary tumour and malignant ascites, promoting tumour growth, angiogenesis, metastasis, chemotherapy resistance and immunosuppression. Differential microRNA (miRNA) profiles have been implicated in the plasticity of TAMs. Therefore, delivering miRNA to TAMs to promote an anti-tumour phenotype is a novel approach to reverse their pro-tumour activity and enhance the efficacy of cancer immunotherapies. Oncolytic viruses (OVs) preferentially replicate in tumour cells making them ideal vehicles to deliver miRNA mimetics to the TME. Importantly, miRNA expressed by OVs get packaged within tumour-derived extracellular vesicles (TDEVs), and release of TDEV is augmented by OV infection, thus enhancing the dissemination of miRNA throughout the TME.MethodSmall RNA sequencing was used to identify differentially expressed miRNA during TAM generation and following LPS/IFNγ stimulation to induce an anti-tumour phenotype. Two differentially expressed miRNA identified, miR-155 and miR-19a, were cloned into oncolytic rhabdovirus (ORV), and anti-tumour efficacy was investigated using both in vitro and in vivo models of OvCa.ResultsThis study demonstrates that ORV infection enhances TDEV production in OvCa cell lines both in vitro and in vivo and that TDEV are preferentially taken up by myeloid cells, including TAMs. Small RNA sequencing identified 23 miRNAs that were significantly upregulated in anti-tumour TAMs, including miR-155-5p. While 101 miRNAs were downregulated during pro-tumour TAM differentiation, including miR-19a-3p. Culturing TDEV expressing miR-155 or miR-19a with TAMs reversed their immunosuppressive activity, as measured by T cell proliferation. While ORV-miR-155 enhanced the generation of anti-tumour T cells, only ORV-miR19a significantly improved survival of mice bearing ovarian tumours.ConclusionThis study demonstrates (i) that arming ORVs with immunomodulatory miRNA is an effective approach to deliver miRNA to myeloid cells within the TME and (ii) that miRNA have the capacity to reverse the tumour promoting properties of TAMs and improve the efficacy of cancer immunotherapies, such as OV.

Long term survival and outcomes in patients with paraneoplastic neurologic syndromes

ObjectiveIt is unknown whether delay in diagnosis affects morbidity reportedly in paraneoplastic syndromes (PNS). We aimed to explore various aspects of PNS, including prevalence, clinical characteristics, diagnostic criteria, and treatment outcomes.MethodsWe studied n-PNS diagnosis between 2016 to 2023, and included only patients with positive onconeural antibodies, who developed cancer, and exhibited a recognizable PNS phenotype.ResultsWe identified 12 patients with positive Abs and co-occurring cancer, most prevalent PNS antibodies included anti-GAD65, anti-Recoverin and anti-Yo. The most common phenotypes were limbic encephalitis (n=5, 42%) and encephalomyelitis (n=4,33%). Cancer preceded neurological presentation in 6 cases. Among the 6 patients who initially presented with n-PNS, median time from neurological presentation to oncologic diagnosis was 73 days, as five of them (83%) were diagnosed with cancer during oncological evaluation prompted by the PNS diagnosis or suspicion. Lymphoma was the most frequent cancer (n=3, 25%), followed by lung cancer (n=2, 17%), and ovarian cancer (n=2, 17%). Among patients who received immunotherapy as n-PNS treatment (n=9, 75%), steroids were a part of the management at 78% (n=7). Another immunotherapy used included plasmapheresis (n=5, 55%) and steroid sparing immunosuppressant (n=2, 29%). Four (33%) patients had short term therapeutic benefit with improvement or stabilization at mRS ≤ 4. Median Disability-adjusted life years (DALYs), as disease burden value, was 13 years. Death occurred in 9 of the 12 patients, with most cases deaths attributed to cancer progression. Compering to the expected median survival by type and stage of tumor, from 9 deceased patients, 56% (n=5) died younger than expected. Median survival was 410 days (range 29-2738 days), and 152 days since the appearance of n-PNS (range 8-1434 days). There were no differences in survival between patients who initially presented with n-PNS versus cancer (p=0.39).ConclusionIn up to 8 years of follow up, there was no difference in mortality among patients who presented initially n-PNS. There was a significant decline in the quality of life, most face substantial disability and functional impairment long term.

Organoid models of ovarian cancer: resolving immune mechanisms of metabolic reprogramming and drug resistance

Metabolic reprogramming is a hallmark of ovarian cancer, enabling tumor progression, immune evasion and drug resistance. The tumor microenvironment (TME) further shapes metabolic adaptations, enabling cancer cells to withstand hypoxia and nutrient deprivation. While organoid models provide a physiologically relevant platform for studying these processes, they still lack immune and vascular components, limiting their ability to fully recapitulate tumor metabolism and drug responses. In this study, we investigated the key metabolic mechanisms involved in ovarian cancer progression, focusing on glycolysis, lipid metabolism and amino acid metabolism. We integrated metabolomic analyses and drug sensitivity assays to explore metabolic-TME interactions using patient-derived, adult stem cell-derived and iPSC-derived organ tissues. Among these, we found that glycolysis, lipid metabolism and amino acid metabolism play a central role in tumor progression and chemotherapy resistance. We identified methylglyoxal (MGO)-mediated BRCA2 dysfunction as a driver of immune escape, a role for sphingolipid signaling in tumor proliferation and a role for kynurenine metabolism in CD8+ T cell suppression. In addition, PI3K/AKT/mTOR and Wnt/β-catenin pathways promote chemoresistance through metabolic adaptation. By elucidating the link between metabolic reprogramming and immune evasion, this study identifies key metabolic vulnerabilities and potential drug targets in ovarian cancer. Our findings support the development of metabolically targeted therapies and increase the utility of organoid-based precision medicine models.

Integrated machine learning and single-cell analysis reveal the prognostic and therapeutic potential of SUMOylation-related genes in ovarian cancer

IntroductionOvarian cancer (OC) exhibits high mortality and chemoresistance rates, underscoring the urgent need for precise prognostic biomarkers and novel therapeutic targets. SUMOylation, crucial in cellular stress responses, is frequently dysregulated in various cancers. This study aims to characterize SUMOylation and its regulators in OC and identify potential biomarkers and therapeutic targets.MethodsIn this study, using multi-omics data, we characterized the unique features of SUMOylation in OC and revealed the association between SUMOylation-related genes (SRGs) and OC malignancy. We conducted integrated machine learning and single-cell RNA sequencing data analysis to identify key SRGs and explored their functional characteristics. The prognostic potential of these SRGs was confirmed in ID8 mouse models and in samples from 213 OC patients at West China Second Hospital.ResultsAn integrated machine learning framework identified 22 prognostic-related SRGs from the TCGA-OV cohort. Further single-cell analysis refined these findings, pinpointing five SRGs as biomarkers closely associated with OC cell function, metabolism and the tumor microenvironment. In cancer cells, the expression of four SRGs (PI3, AUP1, CD200 and GNAS) is closely associated with epigenetic regulation and epithelial-mesenchymal signaling. Notably, we found that AUP1 overexpression may contribute to chemoresistance in OC. In the tumor microenvironment, CD8+ cytotoxic T cell with high CCDC80 (another SRG) expression exhibit inhibited cytotoxicity activity. DiscussionOverall, five SRGs were identified and further evaluated as potential prognostic and therapeutic targets, offering deeper insights into precision oncology for OC.

The potential of ME1 in guiding immunotherapeutic strategies for ovarian cancer: insights from pan-cancer research

ObjectiveME1 catalyzes the conversion of malic acid into acetic acid, thereby linking glucose metabolism to the citric acid cycle. In recent years, the role of ME1 in various tumors has only been superficially explored. Therefore, our objective is to analyze the potential functions of ME1 in pan-cancer, with a particular focus on its role in ovarian cancer.MethodsWe analyzed the ME1 expression levels in both normal and tumor tissues across various cancer types. CBIOPORTAL was utilized to assess the mutation frequency and specific sites of ME1. Additionally, we examined the correlation between ME1 expression and several factors, including methylation status, tumor mutation burden (TMB), microsatellite instability (MSI), immune regulator genes, immune checkpoints, tumor microenvironment scores, functional enrichment, single-cell analysis, and drug sensitivity. The Estimate Algorithm assessed the correlation between ME1 expression and the tumor immunochemical microenvironment. Small interfering RNA and chronic viruses were utilized to downregulate and upregulate ME1 expression in two ovarian cancer cell lines, respectively, to conduct experiments on cell proliferation and migration.ResultsOur results revealed that ME1 exhibited disorders across various tumors, with the predominant form of genetic mutation identified being a missense mutation. Among the various tumors analyzed, ME1 demonstrated a significant correlation with methylation levels, TMB, MSI, immune checkpoints, immunomodulatory regulatory genes, tumor microenvironment scores, and immune infiltration. Functional enrichment analysis and single-cell analysis indicated that ME1 expression was associated with metabolic regulation, macrophage immune responses, antioxidant defense mechanisms, and the potential tumor microenvironment. The elevated levels of ME1 may be associated with a more favorable response to specific immunotherapy, suggesting that ME1 has potential applications in guiding immunotherapeutic strategies. In vitro research results demonstrated that in ovarian cancer cell lines, the knockdown of ME1 inhibited the proliferation and migration of tumor cells. Conversely, the overexpression of ME1 appeared to promote tumor cell proliferation and migration.ConclusionsME1, a metabolic-related factor, has the potential to serve as a biomarker for tumor progression and immune infiltration, particularly in ovarian cancer. It may signify a metabolic reprogramming that supplies energy for tumor progression and immunotherapy, offering valuable insights for the development of personalized therapies.

Increased peritoneal TGF-β1 is associated with ascites-induced NK-cell dysfunction and reduced survival in high-grade epithelial ovarian cancer

Natural killer (NK) cell therapy represents an attractive immunotherapy approach against recurrent epithelial ovarian cancer (EOC), as EOC is sensitive to NK cell-mediated cytotoxicity. However, NK cell antitumor activity is dampened by suppressive factors in EOC patient ascites. Here, we integrated functional assays, soluble factor analysis, high-dimensional flow cytometry cellular component data and clinical parameters of advanced EOC patients to study the mechanisms of ascites-induced inhibition of NK cells. Using a suppression assay, we found that ascites from EOC patients strongly inhibits peripheral blood-derived NK cells and CD34+ progenitor-derived NK cells, albeit the latter were more resistant. Interestingly, we found that higher ascites-induced NK cell inhibition correlated with reduced progression-free and overall survival in EOC patients. Furthermore, we identified transforming growth factor (TGF)-β1 to correlate with ascites-induced NK cell dysfunction and reduced patient survival. In functional assays, we showed that proliferation and anti-tumor reactivity of CD34+ progenitor-derived NK cells are significantly affected by TGF-β1 exposure. Moreover, inhibition of TGF-β1 signaling with galunisertib partly restored NK cell functionality in some donors. For the cellular components, we showed that the secretome is associated with a different composition of CD45+ cells between ascites of EOC and benign reference samples with higher proportions of macrophages in the EOC patient samples. Furthermore, we revealed that higher TGF-β1 levels are associated with the presence of M2-like macrophages, B cell populations and T-regulatory cells in EOC patient ascites. These findings reveal that targeting TGF-β1 signaling could increase NK cell immune responses in high-grade EOC patients.

Chemotherapy driven alterations in NK cell receptors and ligands in high grade serous ovarian cancer

Introduction Combination approaches are being explored to improve immunotherapy efficacy, yet the immunomodulatory effects of chemotherapy on NK cell receptors and their ligands remain unexplored in high-grade serous ovarian cancer (HGSOC). Therefore, understanding chemotherapy-induced immune modulation is essential in HGSOC. Methods Immune profiling was conducted on clinical specimens from 33 chemo-naïve patients undergoing primary debulking surgery (PDS), 57 chemotherapy-treated patients undergoing interval debulking surgery (IDS), and 17 patients in the IDS group were followed during chemotherapy cycles. Immune profiling was carried out using flow cytometry, Procartaplex immunoassay, and ELISA. Blood samples were collected from 50 age- and gender-matched healthy participants for comparison. Results Primary investigation on follow-up patients reveals chemotherapy-mediated immune modulation on NK cell subsets. This was further validated in the chemo-treated surgical cohort. The Natural Cytotoxicity Receptors (NCRs) were downregulated on NK cells in chemo-naïve surgical cohorts. The NCR group of receptors was normalized to a level comparable to that in healthy controls in the chemotherapy-treated surgical cohort, due to reduced soluble ligands. Surface MICA expression was also increased (p = 0.0466) on EpCAM+ cells in the chemo-treated surgical cohort compared to the chemo-naïve surgical cohort, while NKG2D+ immune cells were reduced in both surgical cohorts compared to healthy controls. Moreover, proinflammatory cytokines IL-2 (p = 0.0001) and TNF-α (p = 0.0442) were reduced in the chemotherapy-treated surgical cohort, while intracellular levels of dual perforin and granzyme were elevated in the chemo-treated group, which may enhance cytolytic potential. High surface expressions of HLA-E, MIC-B, and LLT-1 ligands were associated with improved progression-free survival. Conclusions Our findings highlight the broad immunomodulatory effects of chemotherapy on NK cell receptors, ligands, and cytokines, which may offer insights for combination therapies in HGSOC.

Case Report: Two cases of primary malignant melanoma of the female genital tract and literature review

Primary malignant melanoma of the cervix (PMMC) is an exceptionally rare and aggressive malignancy with a poor prognosis. Due to its rarity, there are no standardized treatment guidelines. This case report presents two patients with PMMC, contributing to the literature through a novel treatment approach and literature review. Both patients presented with vaginal bleeding: one postmenopausal without obvious cervical pigmentation, the other premenopausal with a brown, friable cervical mass. Histopathology confirmed PMMC in both. The first patient underwent radical surgery without adjuvant therapy and died from recurrence 36 months later. The second patient received radical surgery, adjuvant chemotherapy, and bevacizumab maintenance, followed by a combination of carboplatin, dacarbazine, and Tislelizumab for pulmonary metastases, achieving significant tumor regression after two cycles. A review of nine reported cases treated with PD-1/PD-L1 inhibitors revealed that radical surgery was performed in 90% of patients, yet 80% did not receive chemotherapy or radiotherapy, and most (80%) still experienced disease progression with immunotherapy, underscoring its limited efficacy. PD-L1 expression, assessed in only three cases (all negative), did not reliably predict response. In conclusion, PMMC remains a formidable clinical challenge with high recurrence rates despite surgery. Response to immune checkpoint inhibitors is inconsistent, but multimodal strategies integrating surgery, chemotherapy, anti-angiogenic agents, and immunotherapy may offer clinical benefit and warrant further investigation to improve outcomes in this aggressive disease.

Advancements in the utilization of immune checkpoint inhibitors for the treatment of gynecological tumors

Immunotherapy, as the fourth major cancer treatment method, has made breakthrough progress in the field of cancer therapy. Immune checkpoint inhibitors (ICIs) have been extensively utilized in the management of diverse malignant neoplasms, with a substantial corpus of clinical evidence and experience accumulating in the field of gynecological oncology. This article reviews the clinical application strategies of ICIs, either alone or in combination with radiotherapy and chemotherapy, targeted therapy, etc., for gynecological malignant tumors such as cervical cancer, endometrial cancer, ovarian cancer, and other malignancies. We summarized relevant progress from clinical trials with the aim of providing more effective precision immunotherapy strategies for patients with gynecological malignant tumors.

A novel mitochondrial autophagy and aging-related gene signature for predicting ovarian cancer

Ovarian cancer (OC) is a highly malignant gynecologic tumor with a poor prognosis. In recent years, mitochondrial autophagy and aging (MiAg) have been recognized as crucial pathophysiological mechanisms leading to tumorigenesis. However, the expression of MiAg-related genes in OC and their correlation with prognosis remain unclear. In this study, we used multiple machine learning methods to identify 52 MiAg genes that were differentially expressed between OC and normal ovarian tissues. Based on these 52 differentially expressed genes (DEGs), 375 OC patients were classified into two subtypes by consensus clustering analysis. Subsequently, we evaluated the prognostic value of MiAg-related genes in relation to survival in 375 OC patients with complete survival information, and developed a MiAg prognostic score model. By applying Cox and LASSO regression methods, a five-gene signature was constructed, and the 375 OC patients in the TCGA cohort were categorized into low-risk and high-risk group based on the median risk score. Meanwhile, we categorized 174 OC patients from the Gene Expression Omnibus (GEO) database into high- and low-risk groups using the median risk score of the TCGA cohort to validate the MiAg scoring model. Furthermore, we analyzed these data with unifactorial and multifactorial analyses, functional enrichment analysis, gene mutation analysis, immune infiltration, drug susceptibility analysis, cell line analysis, and immunohistochemistry data from the HPA database. In conclusion, the MiAgscore predicted patient survival, and lower MiAgscore values were associated with a better survival advantage. A comprehensive assessment of mitochondrial autophagy and cellular senescence alterations in OC could help advance disease target development and provide more effective personalized treatment strategies for OC patients.

The role of macrophage polarization in ovarian cancer: from molecular mechanism to therapeutic potentials

Ovarian cancer (OC) remains the most lethal gynecological malignancy, primarily due to its late-stage diagnosis, frequent recurrence, and resistance to conventional chemotherapy. A critical factor contributing to OC’s aggressiveness is the tumor microenvironment (TME), particularly the presence and polarization of tumor-associated macrophages (TAMs). TAMs, often skewed toward an immunosuppressive M2-like phenotype, facilitate tumor growth, angiogenesis, metastasis, and resistance to therapy. This comprehensive review delves into the multifaceted regulation of macrophage polarization in OC, highlighting key molecular pathways such as PTEN loss, Wnt/β-catenin signaling, NF-κB, Myc, STAT3, and JNK, among others. Additionally, it explores the role of chemokines, non-coding RNAs, and various proteins in modulating TAM phenotypes. Emerging evidence underscores the significance of extracellular vesicles (EVs) and ovarian cancer stem cells (CSCs) in promoting M2 polarization, thereby enhancing tumor progression and therapy resistance. The review also identifies critical biomarkers associated with macrophage polarization, including CD163, LILRB1, MUC2, and others, which hold prognostic and therapeutic potential. Therapeutic strategies targeting TAMs are extensively discussed, encompassing oncolytic viruses, engineered EVs, immunotherapies, nanoparticles, targeted therapies, and natural products. These approaches aim to reprogram TAMs from a pro-tumorigenic M2 state to an anti-tumorigenic M1 phenotype, thereby enhancing immune responses and overcoming resistance to treatments such as chemotherapy and immune checkpoint inhibitors. Furthermore, the review addresses the interplay between macrophage polarization and therapy resistance, emphasizing the need for novel interventions to modulate the TME effectively. By synthesizing current knowledge on macrophage polarization in ovarian cancer, this study underscores the potential of targeting TAMs to improve clinical outcomes and personalize treatment strategies for OC patients. Continued research in this domain is essential to develop robust therapeutic frameworks that can mitigate the immunosuppressive TME and enhance the efficacy of existing and novel cancer therapies.

Oncogenic CMTM6 drives M2a macrophages formation and fuels cervical cancer progression

IntroductionCMTM6, a member of the CKLF like MARVEL transmembrane (CMTM) gene family, has emerged as a critical orchestrator of oncogenic processes, yet its specific role in cervical cancer (CC) remains insufficiently characterized. Mounting evidence implicates that CMTM6 in sculpting an immunosuppressive tumor microenvironment (TME).MethodsWe investigated the expression and functional role of CMTM6 in CC cells using in vitro biological assays and a mouse xenograft model. The impact of CMTM6 on macrophage polarization and its association with tumor progression were systematically evaluated through a series of in vitro and in vivo experiments, focusing on the induction of M2a macrophage polarization and activation of the mTOR signaling pathway.ResultsOur results demonstrate that exosomes secreted by CC cells encapsulate CMTM6, which is actively internalized by macrophages, inducing M2a polarization and triggering immunosuppressive pathways. Excessive macrophage infiltration in the TME, particularly in the presence of CMTM6, is strongly associated with unfavorable prognosis. Furthermore, exosomal CMTM6 activates the mTOR signaling pathway in tumor-associated macrophages, enhancing CCL2 secretion, which further promotes M2a polarization and accelerates tumor metastasis.DiscussionThese findings highlight exosomal CMTM6 as a crucial driver of immune suppression in CC, with the CMTM6/CD206/CCL2 axis significantly increasing the risk for CC patients. Our study underscores the potential of exosomal CMTM6 as both a prognostic biomarker and a therapeutic target for CC immunotherapy.

A surprising complete response to cadonilimab in a primary metastatic cervical cancer: a case report

The outcome of patients with recurrent/metastatic cervical cancer (R/M CC) is poor, with a 5-year survival rate of only 10%–20%. Recent advances in immunotherapy renewed its interest in R/M CC treatment. It has been suggested that cadonilimab, a novel bispecific antibody targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), significantly improved the survival outcomes of the R/M CC. In the present study, we reported a programmed death ligand 1 (PD-L1) and human epidermal growth factor receptor 2 (HER-2) positive CC case at stage IV who was treated with cadonilimab and achieved a surprising radiographic complete response (CR) for 10 months, even in the PD-L1 negative metastatic site. Demographic, clinical, histopathological, laboratory, treatment regime and imaging data were recorded. Unfortunately, the patient progressed rapidly during maintenance therapy when cadonilimab was replaced by sintilimab, the monoclonal antibody against PD-1, indicating the more powerful anti-tumor activity of dual blockade immunotherapy. To conclude, cadonilimab offers a promising and effective therapeutic approach for R/M CC. Notably, HER-2 is also expected to be a new reference target for cadonilimab therapy.

PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer

Recurrent disease emerges in the majority of patients with ovarian cancer (OVCA). Adoptive T-cell therapies with T-cell receptors (TCRs) targeting tumor-associated antigens (TAAs) are considered promising solutions for less-immunogenic ‘cold’ ovarian tumors. In order to treat a broader patient population, more TCRs targeting peptides derived from different TAAs binding in various HLA class I molecules are essential. By performing a differential gene expression analysis using mRNA-seq datasets, PRAME, CTCFL and CLDN6 were selected as strictly tumor-specific TAAs, with high expression in ovarian cancer and at least 20-fold lower expression in all healthy tissues of risk. In primary OVCA patient samples and cell lines we confirmed expression and identified naturally expressed TAA-derived peptides in the HLA class I ligandome. Subsequently, high-avidity T-cell clones recognizing these peptides were isolated from the allo-HLA T-cell repertoire of healthy individuals. Three PRAME TCRs and one CTCFL TCR of the most promising T-cell clones were sequenced, and transferred to CD8+ T cells. The PRAME TCR-T cells demonstrated potent and specific antitumor reactivity in vitro and in vivo. The CTCFL TCR-T cells efficiently recognized primary patient-derived OVCA cells, and OVCA cell lines treated with demethylating agent 5-aza-2′-deoxycytidine (DAC). The identified PRAME and CTCFL TCRs are promising candidates for the treatment of patients with ovarian cancer, and are an essential addition to the currently used HLA-A*02:01 restricted PRAME TCRs. Our selection of differentially expressed genes, naturally expressed TAA peptides and potent TCRs can improve and broaden the use of T-cell therapies for patients with ovarian cancer or other PRAME or CTCFL expressing cancers.

Single-cell technologies and spatial transcriptomics: decoding immune low - response states in endometrial cancer

Globally, endometrial cancer continues to impact a significant number of women. Immunotherapy provides those suffering from advanced or relapsed disease hope, but an important barrier is still the absence of trustworthy predictive biomarkers. To tackle this challenge, single-cell sequencing and spatial transcriptomics (ST) are increasingly applied. In cervical cancers of the no specific molecular profile (NSMP) subtype accompanied by p53 mutations. In many cases, the tumor microenvironment (TME) in endometrial cancer exhibits strong immunosuppression or poor immune cell infiltration, often leading to worse clinical outcomes. Single-cell sequencing reveals cellular heterogeneity and helps identify potential therapeutic targets and predict treatment responses. Conversely, ST assists in determining biomarkers that influence the effectiveness of immunotherapy by capturing the spatial organization of tumors. When combined, these technologies allow for integrated multi-omics analysis that aids in the development of immunotherapies, prognostication, and diagnosis. But there are still moral and legal issues. Clinicians may be able to improve outcomes for patients who don’t respond well to current immunotherapies by utilizing these combined approaches.

Human papillomavirus vaccination in low- and middle-income countries: progression, barriers, and future prospective

Human papillomavirus (HPV) is a viral infection that, if does not go away, can cause health problems like genital warts and cancer. The national immunization schedules for individuals before sexual debut, significantly decreased HPV-associated mortality and it will be affordable. However, immunization programs remain vulnerable to macroeconomic factors such as inflation, fiscal policy, employment levels, and national income. This review aims to investigate the association between national income in lower-middle-income countries to explore recent advances and potential issues, as well as how to deal with challenges.

IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation

The immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO1) and the PD-1/PD-L1 axis are potent mechanisms that impede effective anti-tumor immunity in ovarian cancer. However, whether the IDO pathway regulates PD-1 expression in T cells is currently unknown. Here we show that tumoral IDO1 expression led to profound changes in tryptophan, nicotinate/nicotinamide, and purine metabolic pathways in the ovarian tumor microenvironment, and to an increased frequency of PD-1+CD8+ tumor infiltrating T cells. We determined that activation of the aryl hydrocarbon receptor (AHR) by kynurenine induced PD-1 expression, and this effect was significantly abrogated by the AHR antagonist CH223191. Mechanistically, kynurenine alters chromatin accessibility in regulatory regions of T cell inhibitory receptors, allowing AHR to bind to consensus XRE motifs in the promoter region of PD-1. These results enable the design of strategies to target the IDO1 and AHR pathways for enhancing anti-tumor immunity in ovarian cancer.

Identification of prognostic subtypes and the role of FXYD6 in ovarian cancer through multi-omics clustering

BackgroundOvarian cancer (OC), as a malignant tumor that seriously endangers the lives and health of women, is renowned for its complex tumor heterogeneity. Multi-omics analysis, as an effective method for distinguishing tumor heterogeneity, can more accurately differentiate the prognostic subtypes with differences among patients with OC. The aim of this study is to explore the prognostic subtypes of OC and analyze the molecular characteristics among the different subtypes.MethodsWe utilized 10 clustering algorithms to analyze the multi-omics data of OC patients from The Cancer Genome Atlas (TCGA). After that, we integrated them with ten different machine-learning methods in order to determine high-resolution molecular subgroups and generate machine-learning-driven characteristics that are both resilient and consensus-based. Following the application of multi-omics clustering, we were able to identify two cancer subtypes (CSs) that were associated with the prognosis. Among these, CS2 demonstrated the most positive predictive outcome. Subsequently, five genes that constitute the machine learning (ML)-driven features were screened out by ML algorithms, and these genes possess a powerful predictive ability for prognosis. Subsequently, the function of FXYD Domain-Containing Ion Transport Regulator 6 (FXYD6) in OC was analyzed through gene knockdown and overexpression, and the mechanism by which it affects the functions of OC was explored.ResultsThrough multi-omics analysis, we ascertained that the high-risk score group exhibits a poorer prognosis and lack of response to immunotherapy. Moreover, this group is more prone to display the “cold tumor” phenotype, with a lower likelihood of benefiting from immunotherapy. FXYD6, being a crucial differential molecule between subtypes, exerts a tumor-promoting effect when knocked down; conversely, its overexpression yields an opposite outcome. Additionally, we discovered that the overexpression of FXYD6 can induce ferroptosis in OC cells, implying that a low level of FXYD6 in OC cells can safeguard them from ferroptosis. Insightful and more precise molecular categorization of OC can be achieved with a thorough examination of multi-omics data. There are significant consequences for clinical practice stemming from the discovery of risk scores since they provide a useful tool for early prognosis prediction as well as the screening of candidates for immunotherapy.

Single-cell sequencing reveals effects of chemotherapy on the immune landscape and TCR/BCR clonal expansion in a relapsed ovarian cancer patient

Cancer recurrence and chemoresistance are the leading causes of death in high-grade serous ovarian cancer (HGSOC) patients. However, the unique role of the immune environment in tumor progression for relapsed chemo-resistant patients remains elusive. In single-cell resolution, we characterized a comprehensive multi-dimensional cellular and immunological atlas from tumor, ascites, and peripheral blood of a chemo-resistant patient at different stages of treatment. Our results highlight a role in recurrence and chemoresistance of the immunosuppressive microenvironment in ascites, including MDSC-like myeloid and hypo-metabolic γδT cells, and of peripheral CD8+ effector T cells with chemotherapy-induced senescent/exhaustive. Importantly, paired TCR/BCR sequencing demonstrated relative conservation of TCR clonal expansion in hyper-expanded CD8+ T cells and extensive BCR clonal expansion without usage bias of V(D)J genes after chemotherapy. Thus, our study suggests strategies for ameliorating chemotherapy-induced immune impairment to improve the clinical outcome of HGSOC.

Exploration of the underlying biological differences and targets in ovarian cancer patients with diverse immunotherapy response

BackgroundPreclinical trials of immunotherapy in ovarian cancer (OC) have shown promising results. This makes it meaningful to prospectively examine the biological mechanisms explaining the differences in response performances to immunotherapy among OC patients.MethodsOpen-accessed data was obtained from the Cancer Genome Atlas and Gene Expression Omnibus database. All the analysis was conducted using the R software.ResultsWe firstly performed the TIDE analysis to evaluate the immunotherapy response rate of OC patients. The machine learning algorithm LASSO logistic regression and SVM-RFE were used to identify the characteristic genes. The genes DPT, RUNX1T1, PTPRN, LSAMP, FDCSP and COL6A6 were selected for molecular typing. Our result showed that the patients in Cluster1 might have a better prognosis and might be more sensitive to immunotherapy, including PD-1 and CTLA4 therapy options. Pathway enrichment analysis showed that in Cluster2, the pathway of EMT, TNFα/NF-kB signaling, IL2/STAT5 signaling, inflammatory response, KRAS signaling, apical junction, complement, interferon-gamma response and allograft rejection were significantly activated. Also, genomic instability analysis was performed to identify the underlying genomic difference between the different Cluster patients. Single-cell analysis showed that the DPT, COL6A6, LSAMP and RUNX1T1 were mainly expressed in the fibroblasts. We then quantified the CAFs infiltration in the OC samples. The result showed that patients with low CAFs infiltration might have a lower TIDE score and a higher proportion of immunotherapy responders. Also, we found all the characteristic genes DPT, RUNX1T1, PTPRN, LSAMP, FDCSP and COL6A6 were upregulated in the patients with high CAFs infiltration. Immune infiltration analysis showed that the patients in Cluster2 might have a higher infiltration of naive B cells, activated NK cells and resting Dendritic cells.ConclusionsIn summary, our study provides new insights into ovarian cancer immunotherapy. Meanwhile, specific targets DPT, RUNX1T1, PTPRN, LSAMP, FDCSP, COL6A6 and CAFs were identified for OC immunotherapy.

Pan-cancer analyses and molecular subtypes based on the cancer-associated fibroblast landscape and tumor microenvironment infiltration characterization reveal clinical outcome and immunotherapy response in epithelial ovarian cancer

BackgroundCancer-associated fibroblasts (CAFs) are essential components of the tumor microenvironment (TME). These cells play a supportive role throughout cancer progression. Their ability to modulate the immune system has also been noted. However, there has been limited investigation of CAFs in the TME of epithelial ovarian cancer (EOC).MethodsWe comprehensively evaluated the CAF landscape and its association with gene alterations, clinical features, prognostic value, and immune cell infiltration at the pan-cancer level using multi-omic data from The Cancer Genome Atlas (TCGA). The CAF contents were characterized by CAF scores based on the expression levels of seven CAF markers using the R package “GSVA.” Next, we identified the molecular subtypes defined by CAF markers and constructed a CAF riskscore system using principal component analysis in the EOC cohort. The correlation between CAF riskscore and TME cell infiltration was investigated. The ability of the CAF riskscore to predict prognosis and immunotherapy response was also examined.ResultsCAF components were involved in multiple immune-related processes, including transforming growth factor (TGF)-β signaling, IL2-STAT signaling, inflammatory responses, and Interleukin (IL) 2-signal transducer and activator of transcription (STAT) signaling. Considering the positive correlation between CAF scores and macrophages, neutrophils, and mast cells, CAFs may exert immunosuppressive effects in both pan-cancer and ovarian cancer cohorts, which may explain accelerated tumor progression and poor outcomes. Notably, two distinct CAF molecular subtypes were defined in the EOC cohort. Low CAF riskscores were characterized by favorable overall survival (OS) and higher efficacy of immunotherapy. Furthermore, 24 key genes were identified in CAF subtypes. These genes were significantly upregulated in EOC and showed a strong correlation with CAF markers.ConclusionsIdentifying CAF subtypes provides insights into EOC heterogeneity. The CAF riskscore system can predict prognosis and select patients who may benefit from immunotherapy. The mechanism of interactions between key genes, CAF markers, and associated cancer-promoting effects needs to be further elucidated.

A novel tumor mutational burden-based risk model predicts prognosis and correlates with immune infiltration in ovarian cancer

Tumor mutational burden (TMB) has been reported to determine the response to immunotherapy, thus affecting the patient’s prognosis in many cancers. However, it is unclear whether TMB or TMB-related signature could be used as prognostic indicators for ovarian cancer (OC), as its potential association with immune infiltration remains poorly understood. Therefore, this study aimed to develop a novel TMB-related risk model (TMBrisk) to predict the prognosis of OC patients on the basis of exploring TMB-related genes, and to explore the potential association between TMB/TMBrisk and immune infiltration. The mutational landscape, TMB scores, and correlations between TMB and clinical characteristics and immune infiltration were investigated in The Cancer Genome Atlas (TCGA)-OV cohort. Differentially expressed gene (DEG) analyses and weighted gene co-expression network analysis (WGCNA) were performed to derive TMB-related genes. TMBrisk was constructed by Cox regression and further validated in Gene Expression Omnibus (GEO) datasets. The mRNA and protein expression levels and biological functions of TMBrisk hub genes were verified through Gene Expression Profiling Interactive Analysis (GEPIA), GSCA Lite, the Human Protein Atlas (HPA) database, and RT-qPCR. TMBrisk-related biological phenotypes were analyzed in function enrichment and tumor immune infiltration signature. Potential therapeutic regimens were inferred utilizing the Genomics of Drug Sensitivity in Cancer (GDSC) database and connectivity map (CMap). According to our results, higher TMB was associated with better survival and higher CD8+ T cell, regulatory T cell, and NK cell infiltration. TMBrisk was developed based on CBWD1, ST7L, RFX5-AS1, C3orf38, LRFN1, LEMD1, and HMGB1. High TMBrisk was identified as a poor factor for prognosis in TCGA and GEO datasets; the high-TMBrisk group comprised more higher-grade (G2 and G3) and advanced clinical stage (stage III/IV) tumors. Meanwhile, higher TMBrisk was associated with an immunosuppressive phenotype, with less infiltration of a majority of immunocytes and less expression of several genes of the human leukocyte antigen (HLA) family. Moreover, a nomogram containing TMBrisk showed a strong predictive ability demonstrated by time-dependent ROC analysis. Overall, this novel TMB-related risk model (TMBrisk) could predict prognosis, evaluate immune infiltration, and discover new therapeutic regimens in OC, which is very promising in clinical promotion.

Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

Ovarian cancer (OC) is one of the most common malignancies that causes death in women and is a heterogeneous disease with complex molecular and genetic changes. Because of the relatively high recurrence rate of OC, it is crucial to understand the associated mechanisms of drug resistance and to discover potential target for rational targeted therapy. Cell death is a genetically determined process. Active and orderly cell death is prevalent during the development of living organisms and plays a critical role in regulating life homeostasis. Ferroptosis, a novel type of cell death discovered in recent years, is distinct from apoptosis and necrosis and is mainly caused by the imbalance between the production and degradation of intracellular lipid reactive oxygen species triggered by increased iron content. Necroptosis is a regulated non-cysteine protease–dependent programmed cell necrosis, morphologically exhibiting the same features as necrosis and occurring via a unique mechanism of programmed cell death different from the apoptotic signaling pathway. Pyroptosis is a form of programmed cell death that is characterized by the formation of membrane pores and subsequent cell lysis as well as release of pro-inflammatory cell contents mediated by the abscisin family. Studies have shown that ferroptosis, necroptosis, and pyroptosis are involved in the development and progression of a variety of diseases, including tumors. In this review, we summarized the recent advances in ferroptosis, necroptosis, and pyroptosis in the occurrence, development, and therapeutic potential of OC.

CAR T cells targeting the ganglioside NGcGM3 control ovarian tumors in the absence of toxicity against healthy tissues

Chimeric antigen receptor (CAR) T cells have emerged as a powerful immunotherapeutic tool against certain hematological malignancies but a significant proportion of patients either do not respond or they relapse, sometimes as a result of target antigen loss. Moreover, limited clinical benefit has been reported for CAR therapy against epithelial derived solid tumors. A major reason for this is the paucity of solid tumor antigens identified to date that are broadly, homogeneously and stably expressed but not found on healthy tissues. To address this, here we describe the development and evaluation of CAR T cells directed against N-glycoslylated ganglioside monosialic 3 (NGcGM3). NGcGM3 derives from the enzymatic hydroxylation of N-acetylneuraminic acid (NAc) GM3 (NAcGM3) and it is present on the surface of a range of cancers including ovarian, breast, melanoma and lymphoma. However, while NAcGM3 is found on healthy human cells, NGcGM3 is not due to the 7deletion of an exon in the gene encoding for the enzyme cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH). Indeed, unlike for most mammals, in humans NGcGM3 is considered a neoantigen as its presence on tumors is the result of metabolic incorporation from dietary sources. Here, we have generated 3 CARs comprising different single chain variable fragments (scFvs) originating from the well-characterized monoclonal antibody (mAb) 14F7. We show reactivity of the CAR T cells against a range of patient tumor fragments and we demonstrate control of NGcGM3+ SKOV3 ovarian tumors in the absence of toxicity despite the expression of CMAH and presence of NGcGM3+ on healthy tissues in NSG mice. Taken together, our data indicate clinical potential for 14F7-based CAR T cells against a range of cancers, both in terms of efficacy and of patient safety.

Crosstalk of RNA Adenosine Modification-Related Subtypes, Establishment of a Prognostic Model, and Immune Infiltration Characteristics in Ovarian Cancer

BackgroundFour RNA adenosine modifications, including m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, have been identified as potentially valuable in influencing colorectal carcinogenesis, immune infiltration, and response to drug therapy. However, the regulatory mechanisms and clinical significance of these four RNA modifications in ovarian cancer (OC) remain unknown.MethodsWe comprehensively described the transcriptional and genetic modifications of 26 RNA modification “writers” in OC and assessed the expression patterns. We identified two RNA modification subtypes using an unsupervised clustering approach. Subsequently, using differentially expressed genes (DEGs) in both subtypes, we calculated RNA modification “writer” scores (RMW scores) to characterize the RNA modifications of single OC patients. RMW score-related gene expression was investigated by qRT-PCR. We explored the correlation between RMW score and clinical features, immune infiltration, and drug sensitivity. We drew a nomogram to more intuitively and accurately describe the application value of the RMW score.ResultsWe found that molecular alterations in “writers” are strongly related to prognostic and immune-infiltrating features in OC patients. We identified two different clusters of RNA modifications. According to the immune infiltration characteristics in the two RNA modification isoforms, cluster A and cluster B can correspond to “hot” and “cold” tumors, respectively. With the median RMW score, we classified the patients into high- and low-score subgroups. A low RMW score was associated with good patient prognosis and lower immune infiltration. In addition, a low RMW score equated with a higher cancer stem cell index and a lower tumor mutation burden, which to some extent affected the sensitivity of patients to therapeutic drugs. Seven RMW score-related gene expressions were investigated by qRT-PCR in three OC cell lines. Compared to previously known models, our established RMW score has higher accuracy in predicting patient survival.ConclusionA comprehensive analysis of four RNA modification patterns in OC reveals their potential value in OC prognosis, immune microenvironment, and drug sensitivity. These results could deepen our knowledge of RNA modification and yield fresh insights for new personalized therapeutic strategies.

Integrative Analysis From Multicenter Studies Identifies a WGCNA-Derived Cancer-Associated Fibroblast Signature for Ovarian Cancer

Cancer-associated fibroblasts (CAFs) are a major contributor to tumor stromal crosstalk in the tumor microenvironment (TME) and boost tumor progression by promoting angiogenesis and lymphangiogenesis. This study aimed to identify prognostic genes associated with CAFs that lead to high morbidity and mortality in ovarian cancer (OC) patients. We performed bioinformatics analysis in 16 multicenter studies (2,742 patients) and identified CAF-associated hub genes using the weighted gene co-expression network analysis (WGCNA). A machine learning methodology was used to identify COL16A1, COL5A2, GREM1, LUM, SRPX, and TIMP3 and construct a prognostic signature. Subsequently, a series of bioinformatics algorithms indicated risk stratification based on the above signature, suggesting that high-risk patients have a worse prognosis, weaker immune response, and lower tumor mutational burden (TMB) status but may be more sensitive to routine chemotherapeutic agents. Finally, we characterized prognostic markers using cell lines, immunohistochemistry, and single-cell sequencing. In conclusion, these results suggest that the CAF-related signature may be a novel pretreatment guide for anti-CAFs, and prognostic markers in CAFs may be potential therapeutic targets to inhibit OC progression.

Identification and Verification of Necroptosis-Related Gene Signature With Prognosis and Tumor Immune Microenvironment in Ovarian Cancer

Ovarian cancer is the most lethal heterogeneous disease among gynecological tumors with a poor prognosis. Necroptosis, the most studied way of death in recent years, is different from apoptosis and pyroptosis. It is a kind of regulated programmed cell death and has been shown to be closely related to a variety of tumors. However, the expression and prognosis of necroptosis-related genes in ovarian cancer are still unclear. Our study therefore firstly identified the expression profiles of necroptosis-related genes in normal and ovarian cancer tissues. Next, based on differentially expressed necroptosis-related genes, we clustered ovarian cancer patients into two subtypes and performed survival analysis. Subsequently, we constructed a risk model consisting of 5 genes by LASSO regression analysis based on the differentially expressed genes in the two subtypes, and confirmed the strong prognostic ability of the model and its potential as an independent risk factor via survival analysis and independent risk factor analysis. Based on this risk model, patients were divided into high and low risk groups. By exploring differentially expressed genes, enrichment functions and tumor immune microenvironment in patients in high and low risk groups, the results showed that patients in the low risk group were significantly enriched in immune signaling pathways. Besides, immune cells content, immune function activity was significantly better than the high-risk group. Eventually, we also investigated the sensitivity of patients with different risk groups to ICB immunotherapy and chemotherapy drugs. In conclusion, the risk model could effectively predict the survival and prognosis of patients, and explore the tumor microenvironment status of ovarian cancer patients to a certain extent, and provide promising and novel molecular markers for clinical diagnosis, individualized treatment and immunotherapy of patients.

Combination Vaccination With Tetanus Toxoid and Enhanced Tumor-Cell Based Vaccine Against Cervical Cancer in a Mouse Model

Cervical cancer is the fourth most common cancer in women with an estimated 570,000 new cases in 2018 which constitute about 6. 6% of all cancers in women according to WHO report 2018. Approximately 90% of the 270,000 deaths from cervical cancer in 2015 occurred in low- and middle-income countries. In cervical cancers, which is caused by human papillomavirus (HPV) infection, the expression of HPV 16 E6 and E7 proteins are essential for tumor cell transformation and maintenance of malignancy. Prophylactic vaccines against cervical cancer caused by human papillomavirus have not proven successful. Although virus-like particle-based (VLPs) vaccines have been developed with prophylactic activities to prevent most HPV infections, the therapeutic effect of VLP vaccines has yet to be demonstrated for those who were already infected. A recent study showed that pre-conditioning mice with a potent antigen such as tetanus toxoid significantly improves lymph node homing and efficacy of dendritic cells. Tetanus toxoid has also been used in combination with DNA vaccines designed from tumor based antigens. In the present study, we pre-conditioned mice with tetanus toxoid followed by vaccination with a Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) overexpressing tumor-cell based vaccine (GVAX). We observed that pre-conditioning with tetanus toxoid followed by vaccination with GVAX regressed tumor growth and enhanced the overall survival of the mice. Pre-conditioning with tetanus toxoid enhanced the immune response which was observed by enlarged spleen size, higher proliferation rate of lymphocytes, a higher level of IFN-γ, TNF-α, and IL-4 antigen-specific secretions by the splenocytes. Pre-conditioning with tetanus toxoid increased memory T cell migration into the tumor site and spleen. The antigen-specific cytotoxic T cell lysis percentage was also found to be higher in the group of mice vaccinated with the combination of tetanus toxoid and GVAX. Hence, pre-conditioning with tetanus toxoid prior to vaccination with a tumor-cell based vaccine overexpressing GM-CSF might be an effective strategy for targeting E7-specific HPV-associated cervical malignancy.

CD40 Accelerates the Antigen-Specific Stem-Like Memory CD8+ T Cells Formation and Human Papilloma Virus (HPV)-Positive Tumor Eradication

Antigen-specific stem-like memory CD8

Four Types of RNA Modification Writer-Related lncRNAs Are Effective Predictors of Prognosis and Immunotherapy Response in Serous Ovarian Carcinoma

Serous ovarian carcinoma (SOC) is a gynecological malignancy with high mortality rates. Currently, there is a lack of reliable biomarkers for accurate SOC patient prognosis. Here, we analyzed SOC RNA-Seq data from The Cancer Genome Atlas (TCGA) to identify prognostic biomarkers. Through the pearson correlation analysis, univariate Cox regression analysis, and LASSO-penalized Cox regression analysis, we identified nine lncRNAs significantly associated with four types of RNA modification writers (m6A, m1A, APA, and A-I) and with the prognosis of SOC patients (P <0.05). Six writer-related lncRNAs were ultimately selected following multivariate Cox analysis. We established a risk prediction model based on these six lncRNAs and evaluated its prognostic value in multiple groups (training set, testing set, and entire set). Our risk prediction model could effectively predict the prognosis of SOC patients with different clinical characteristics and their responses to immunotherapy. Lastly, we validated the predictive reliability and sensitivity of the lncRNA-based model via a nomogram. This study explored the association between RNA modification writer-related lncRNAs and SOC prognosis, providing a potential complement for the clinical management of SOC patients.

Computed Tomography Imaging-Based Radiogenomics Analysis Reveals Hypoxia Patterns and Immunological Characteristics in Ovarian Cancer

PurposeThe hypoxic microenvironment is involved in the tumorigenesis of ovarian cancer (OC). Therefore, we aim to develop a non-invasive radiogenomics approach to identify a hypoxia pattern with potential application in patient prognostication.MethodsSpecific hypoxia-related genes (sHRGs) were identified based on RNA-seq of OC cell lines cultured with different oxygen conditions. Meanwhile, multiple hypoxia-related subtypes were identified by unsupervised consensus analysis and LASSO–Cox regression analysis. Subsequently, diversified bioinformatics algorithms were used to explore the immune microenvironment, prognosis, biological pathway alteration, and drug sensitivity among different subtypes. Finally, optimal radiogenomics biomarkers for predicting the risk status of patients were developed by machine learning algorithms.ResultsOne hundred forty sHRGs and three types of hypoxia-related subtypes were identified. Among them, hypoxia-cluster-B, gene-cluster-B, and high-risk subtypes had poor survival outcomes. The subtypes were closely related to each other, and hypoxia-cluster-B and gene-cluster-B had higher hypoxia risk scores. Notably, the low-risk subtype had an active immune microenvironment and may benefit from immunotherapy. Finally, a four-feature radiogenomics model was constructed to reveal hypoxia risk status, and the model achieved area under the curve (AUC) values of 0.900 and 0.703 for the training and testing cohorts, respectively.ConclusionAs a non-invasive approach, computed tomography-based radiogenomics biomarkers may enable the pretreatment prediction of the hypoxia pattern, prognosis, therapeutic effect, and immune microenvironment in patients with OC.

Development of a Dendritic Cell/Tumor Cell Fusion Cell Membrane Nano-Vaccine for the Treatment of Ovarian Cancer

Ovarian cancer (OC) is a malignant tumor that seriously affects women’s health. In recent years, immunotherapy has shown great potential in tumor treatment. As a major contributor of immunotherapy, dendritic cells (DCs) - based tumor vaccine has been demonstrated to have a positive effect in inducing immune responses in animal experiments. However, the effect of tumor vaccines in clinical trials is not ideal. Therefore, it is urgent to improve the existing tumor vaccines for tumor treatment. Here, we developed a fusion cell membrane (FCM) nano-vaccine FCM-NPs, which is prepared by fusing DCs and OC cells and coating the FCM on the poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with the immune adjuvant CpG-oligodeoxynucleotide (CpG-ODN). The fusion process promoted the maturation of DCs, thus up-regulating the expression of costimulatory molecule CD80/CD86 and accelerating lymph node homing of DCs. Furthermore, FCM-NPs has both the immunogenicity of tumor cells and the antigen presenting ability of DCs, it can stimulate naive T lymphocytes to produce a large number of tumor-specific cytotoxic CD8+ T lymphocytes. FCM-NPs exhibited strong immuno-activating effect both in vitro and in vivo. By establishing subcutaneous transplanted tumor model, patient-derived xenograft tumor model and abdominal metastatic tumor model, FCM-NPs was proved to have the effect of delaying the growth and inhibiting the metastasis of OC. FCM-NPs is expected to become a new tumor vaccine for the treatment of ovarian cancer.

HPV Induces Changes in Innate Immune and Adhesion Molecule Markers in Cervical Mucosa With Potential Impact on HIV Infection

While most HPV infections are asymptomatic and clear spontaneously, persistent infection with high-risk HPVs is associated with cervical cancer and with increased risk of HIV acquisition. Although several hypotheses have been proposed to explain this phenomenon, none has been confirmed. Our aim was to investigate the expression of host factors involved in the susceptibility to HIV infection among HPV-infected women. Cervical samples were collected to characterize the expression levels of HIV susceptibility markers in the mucosa of HPV-infected compared with HPV-uninfected women. No differences in the frequency of CCR5+, integrin α4β7+, activated and memory CD4+ T-cell were detected between the groups. We additionally evaluated the expression levels of genes involved in innate immune responses and in cell adhesion. HPV infected patients expressed higher levels of TLR9 and lower levels of pattern recognition receptors that recognize RNA (TLR3, TLR7, and MDA5/IFIH1). We also detected an impaired IFN pathway, with an increased Type I IFN and a decreased IFNα2 receptor expression. HPV+ samples displayed reduced expression of genes for adherens and tight junctions. Taken together, these results suggest that although HPV infection does not result in the recruitment/activation of susceptible CD4+ T-cell in the female genital tract, it leads to changes in the innate antiviral immune responses and in cell adhesion that are likely to favor HIV infection.

Progress in Vaccination of Prophylactic Human Papillomavirus Vaccine

The human papillomavirus (HPV) vaccine plays an important role in preventing a series of diseases caused by HPV. Recent studies have shown that as a primary prevention measure, it can considerably prevent HPV infection and HPV-associated cervical cancer. However, studies on the safety, efficacy, and coverage of the HPV vaccine remain insufficient, especially in developing countries. Therefore, in this review, we outlined the recent studies of the HPV vaccine in terms of immunogenicity, safety, efficacy, latest vaccination concepts, and strategies. This review may provide a theoretical basis for use of the HPV vaccine.

Postpartum HPV Vaccination Rate and Differences in Background Characteristics Between HPV Vaccinated and Unvaccinated Postpartum Women: Strict Monitoring and Follow-Up of Postpartum HPV Vaccination Program

There is a need to increase the vaccine completion rates in women who have already received human papillomavirus (HPV) vaccines. With vaccines requiring multiple doses, designing a vaccination control program and increasing the proportion of women who complete vaccination are critical and remain as huge challenges. Currently, there are no published reports on the differences in the background characteristics between postpartum women who are vaccinated or unvaccinated against HPV. This study aimed to determine the vaccination rates of the second and third doses of HPV vaccination utilizing an achievable HPV vaccination program in postpartum women. In this retrospective study, 243 postpartum women attending Chiayi Chang Gung Memorial Hospital between March and September 2014 were enrolled. These women were classified into two groups: one group received the HPV vaccine under a practical, controlled postpartum HPV vaccination program, and the other group did not. The rates for the second and third rounds of HPV vaccination in postpartum women were calculated. The differences in the background characteristics between the two groups were determined using the Student’s t test, chi-square test or Fisher’s exact test, and the multiple logistic models, as appropriate. Under the controlled postpartum HPV vaccination program, the completion rate for the three doses of postpartum HPV vaccination was 97.2%. Significant differences were observed according to maternal age, gender of the newborn, and postpartum Pap smear results between the two groups in our study. In conclusion, the controlled postpartum HPV vaccination program is a reasonable method for achieving an excellent completion rate for the three doses of postpartum HPV vaccination and may be a good model for any multiple-dose vaccination protocol.

The Role of HLA-G in Human Papillomavirus Infections and Cervical Carcinogenesis

Human leukocyte antigen (HLA)-G, a non-classical HLA-class I molecule, has a low polymorphism frequency, restricted tissue distribution and immunoinhibitory property. HLA-G expression in tumor cells and cells chronically infected with virus may enable them to escape from host immune surveillance. It is well-known that the HLA-G molecule is a novel biomarker and potential therapeutic target that is relevant in various types of cancers, but its role in cervical cancer has not been fully explored. In this review, we aim to summarize and discuss the immunologic role of the HLA-G molecule in the context of HPV infections and the process of cervical cancer carcinogenesis. A better understanding of the potential impact of HLA-G on the clinical course of persistent HPV infections, cervical epithelial cell transformation, tumor growth, recurrence and metastasis is needed to identify a novel diagnostic/prognostic biomarker for cervical cancer, which is critical for cervical cancer risk screening. In addition, it is also necessary to identify HLA-G-driven immune mechanisms involved in the interactions between host and virus to explore novel immunotherapy strategies that target HLA-G/immunoglobulin-like transcript (ILT) immune checkpoints.

A Potential Herbal Adjuvant Combined With a Peptide-Based Vaccine Acts Against HPV-Related Tumors Through Enhancing Effector and Memory T-Cell Immune Responses

Viral infection is associated with many types of tumorigenesis, including human papillomavirus (HPV)-induced cervical cancer. The induction of a specific T-cell response against virus-infected cells is desired to develop an efficient therapeutic approach for virus-associated cancer. Chinese herbal medicine (CHM) has a long history in the treatment of cancer patients in Asian countries.

Bevacizumab-induced immune thrombocytopenia in an ovarian cancer patient with mixed connective tissue disease: case report and literature review

Drug-induced immune thrombocytopenia is an adverse reaction marked by accelerated destruction of blood platelets. In cancer therapy, thrombocytopenia has many other causes including bone marrow suppression induced by chemotherapeutic agents, infection, and progression of cancer; drug-induced thrombocytopenia can easily be misdiagnosed or overlooked. Here, we present a case of an ovarian cancer patient with a history of mixed connective tissue disease who underwent surgery followed by treatment with paclitaxel, cisplatin, and bevacizumab. The patient developed acute isolated thrombocytopenia after the sixth cycle. Serum antiplatelet antibody testing revealed antibodies against glycoprotein IIb. After we analyzed the whole therapeutic process of this patient, drug-induced immune thrombocytopenia was assumed, and bevacizumab was conjectured as the most probable drug. Thrombocytopenia was ultimately successfully managed using recombinant human thrombopoietin, prednisone, and recombinant human interleukin-11. We provide a summary of existing literature on immune thrombocytopenia induced by bevacizumab and discuss related mechanisms and triggers for drug-induced immune thrombocytopenia. The present case underscores the potential of bevacizumab to induce immune-mediated thrombocytopenia, emphasizing the need for heightened vigilance towards autoimmune diseases or an autoimmune-activated state as plausible triggers for rare drug-induced immune thrombocytopenia in cancer therapy.

T Cell Receptor Repertoires Acquired via Routine Pap Testing May Help Refine Cervical Cancer and Precancer Risk Estimates

Cervical cancer is the fourth most common cancer and fourth leading cause of cancer death among women worldwide. In low Human Development Index settings, it ranks second. Screening and surveillance involve the cytology-based Papanicolaou (Pap) test and testing for high-risk human papillomavirus (hrHPV). The Pap test has low sensitivity to detect precursor lesions, while a single hrHPV test cannot distinguish a persistent infection from one that the immune system will naturally clear. Furthermore, among women who are hrHPV-positive and progress to high-grade cervical lesions, testing cannot identify the ~20% who would progress to cancer if not treated. Thus, reliable detection and treatment of cancers and precancers requires routine screening followed by frequent surveillance among those with past abnormal or positive results. The consequence is overtreatment, with its associated risks and complications, in screened populations and an increased risk of cancer in under-screened populations. Methods to improve cervical cancer risk assessment, particularly assays to predict regression of precursor lesions or clearance of hrHPV infection, would benefit both populations. Here we show that women who have lower risk results on follow-up testing relative to index testing have evidence of enhanced T cell clonal expansion in the index cervical cytology sample compared to women who persist with higher risk results from index to follow-up. We further show that a machine learning classifier based on the index sample T cells predicts this transition to lower risk with 95% accuracy (19/20) by leave-one-out cross-validation. Using T cell receptor deep sequencing and machine learning, we identified a biophysicochemical motif in the complementarity-determining region 3 of T cell receptor β chains whose presence predicts this transition. While these results must still be tested on an independent cohort in a prospective study, they suggest that this approach could improve cervical cancer screening by helping distinguish women likely to spontaneously regress from those at elevated risk of progression to cancer. The advancement of such a strategy could reduce surveillance frequency and overtreatment in screened populations and improve the delivery of screening to under-screened populations.

HPV-16 E7-Specific Cellular Immune Response in Women With Cervical Intraepithelial Lesion Contributes to Viral Clearance: A Cross-Sectional and Longitudinal Clinical Study

High-risk human papillomavirus (HPV) infection is the cause of almost all cervical cancers. HPV16 is one of the main risk subtypes. Although screening programs have greatly reduced the prevalence of cervical cancer in developed countries, current diagnostic tests cannot predict if mild lesions may progress into invasive lesions or not. In the current cross-sectional and longitudinal clinical study, we found that the HPV16 E7-specific T cell response in peripheral blood mononuclear cells of HPV16-infected patients is related to HPV16 clearance. It contributes to protecting the squamous interaepithelial lesion (SIL) from further malignant development. Of the HPV16 infected women enrolled (n = 131), 42 had neither intraepithelial lesion nor malignancy (NILM), 33 had low-grade SIL, 39 had high-grade SIL, and 17 had cervical cancer. Only one of 17 (5.9%) cancer patients had a positive HPV16 E7-specific T cell response, dramatically lower than the groups of precancer patients. After one year of follow-up, most women (28/33, 84.8%) with persistent HPV infection did not exhibit a HPV16 E7-specific T cell response. Furthermore, 3 malignantly progressed women, one progressed to high-grade SIL and two progressed to low-grade SIL, were negative to the HPV16 E7-specific T cell response. None of the patients with a positive HPV16 E7-specific T cell response progressed to further deterioration. Our observation suggests that HPV16 E7-specific T cell immunity is significant in viral clearance and contributes in protection against progression to malignancy.

Tertiary lymphoid structures: exploring opportunities to improve immunotherapy in ovarian cancer

Tertiary lymphoid structures (TLS) are organized ectopic lymphoid clusters of immune cells that develop in non-lymphoid tissue to promote antigen presentation, drive cytotoxic immune responses, and enhance humoral immunity via B cell clonal expansion. Their presence within the tumor microenvironment (TME) correlates with increased patient survival and an improved response to immune checkpoint inhibitors (ICIs), positioning TLS as potential predictive and prognostic biomarkers. Despite the widespread use of ICIs across various cancers, their effectiveness remains limited in gynecological malignancies, including ovarian cancer (OC), a notably challenging disease characterized by poor responses to both single and combination ICI therapies. Interestingly, the infiltration of T cells into the OC TME is linked to enhanced progression-free survival (PFS) and overall survival (OS), yet an immunosuppressive TME frequently impedes therapeutic efficacy, suggesting cell activity within localized immune niches can impact antitumor immunity. This review explores the roles of TLS, their maturity, functionality, identification, and related gene signatures; specific immune cells and cytokines that play a role in TLS formation and antitumor response; and other modifiable elements, including gut microbiota, that may drive improving OC survival by leveraging a TLS-driven antitumor response to bolster immunotherapy outcomes.

Depletion of Human Papilloma Virus E6- and E7-Oncoprotein-Specific T-Cell Responses in Women Living With HIV

BackgroundCervical cancer - caused by persistent High Risk Human Papilloma Virus (HR HPV) infections - is the second most common cancer affecting women globally. HIV infection increases the risk for HPV persistence, associated disease progression and malignant cell transformation. We therefore hypothesized that this risk increase is directly linked to HIV infection associated dysfunction or depletion of HPV-oncoprotein-specific T-cell responses.MethodsThe 2H study specifically included HIV+ and HIV- women with and without cervical lesions and cancer to analyze HPV oncogene-specific T cell responses in relation to HPV infection, cervical lesion status and HIV status. Oncoprotein E6 and E7 specific T-cell responses were quantified for the most relevant types HPV16, 18 and 45 and control antigens (CMV-pp65) and M.tb-PPD in 373 women, using fresh peripheral blood mononuclear cells in an IFN-γ release ELISpot assay.ResultsOverall, systemic E6- and E7-oncoprotein-specific T-cell responses were infrequent and of low magnitude, when compared to CMV-pp65 and M.tb-PPD (p < 0.001 for all HR HPV types). Within HIV negative women infected with either HPV16, 18 or 45, HPV16 infected women had lowest frequency of autologous-type-E6/E7-specific T-cell responses (33%, 16/49), as compared to HPV18 (46% (6/13), p = 0.516) and HPV45 (69% (9/13), p = 0.026) infected women. Prevalent HPV18 and 45, but not HPV16 infections were linked to detectable oncoprotein-specific T-cell responses, and for these infections, HIV infection significantly diminished T-cell responses targeting the autologous infecting genotype. Within women living with HIV, low CD4 T-cell counts, detectable HIV viremia as well as cancerous and precancerous lesions were significantly associated with depletion of HPV oncoprotein-specific T-cell responses.DiscussionDepletion of HPV-oncoprotein-specific T-cell responses likely contributes to the increased risk for HR HPV persistence and associated cancerogenesis in women living with HIV. The low inherent immunogenicity of HPV16 oncoproteins may contribute to the exceptional potential for cancerogenesis associated with HPV16 infections.

Platinum-based chemotherapy promotes antigen presenting potential in monocytes of patients with high-grade serous ovarian carcinoma

Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide. The major clinical challenge includes the asymptomatic state of the disease, making diagnosis possible only at advanced stages. Another OC complication is the high relapse rate and poor prognosis following the standard first-line treatment with platinum-based chemotherapy. At present, numerous clinical trials are being conducted focusing on immunotherapy in OC; nevertheless, there are still no FDA-approved indications. Personalized decision regarding the immunotherapy, including immune checkpoint blockade and immune cell–based immunotherapies, can depend on the effective antigen presentation required for the cytotoxic immune response. The major aim of our study was to uncover tumor-specific transcriptional and epigenetic changes in peripheral blood monocytes in patients with high-grade serous ovarian cancer (HGSOC). Another key point was to elucidate how chemotherapy can reprogram monocytes and how that relates to changes in other immune subpopulations in the blood. To this end, we performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from patients with HGSOC who underwent neoadjuvant chemotherapeutic treatment (NACT) and in treatment-naïve patients. Monocyte cluster was significantly affected by tumor-derived factors as well as by chemotherapeutic treatment. Bioinformatical analysis revealed three distinct monocyte subpopulations within PBMCs based on feature gene expression – CD14.Mn.S100A8.9hi, CD14.Mn.MHC2hi and CD16.Mn subsets. The intriguing result was that NACT induced antigen presentation in monocytes by the transcriptional upregulation of MHC class II molecules, but not by epigenetic changes. Increased MHC class II gene expression was a feature observed across all three monocyte subpopulations after chemotherapy. Our data also demonstrated that chemotherapy inhibited interferon-dependent signaling pathways, but activated some TGFb-related genes. Our results can enable personalized decision regarding the necessity to systemically re-educate immune cells to prime ovarian cancer to respond to anti-cancer therapy or to improve personalized prescription of existing immunotherapy in either combination with chemotherapy or a monotherapy regimen.

The role of B7-H4 in ovarian cancer immunotherapy: current status, challenges, and perspectives

Immunotherapy stands as a critical and auspicious therapeutic approach in the fight against cancer nowadays. Immune checkpoint inhibitors, in particular, have garnered widespread employment and delivered groundbreaking therapeutic outcomes across various malignancies. However, the efficacy is unsatisfactory in the ovarian cancer. The pressing concerns of the substantial non-response rate require immediate attention. The pursuit of novel targets and the formulation of synergistic combination therapy approaches are imperative for addressing this challenge. B7-H4, a member of the B7 family of co-inhibitory molecules, exhibits high expression levels in ovarian cancer, correlating closely with tumor progression, drug resistance, and unfavorable prognosis. B7-H4 has the potential to serve as a valuable biomarker for evaluating the immune response of patients. Recent investigations and preclinical trials focusing on B7-H4 in the context of ovarian cancer immunotherapy highlight its emergence as a promising immunotherapeutic target. This review aims to discuss these findings and anticipate the future prospects of leveraging B7-H4 in ovarian cancer immunotherapy and targeted therapy.

Ferroptosis: mechanism, immunotherapy and role in ovarian cancer

Ovarian cancer is currently the second most common malignant tumor among gynecological cancers worldwide, primarily due to challenges in early diagnosis, high recurrence rates, and resistance to existing treatments. Current therapeutic options are inadequate for addressing the needs of ovarian cancer patients. Ferroptosis, a novel form of regulated cell death with demonstrated tumor-suppressive properties, has gained increasing attention in ovarian malignancy research. A growing body of evidence suggests that ferroptosis plays a significant role in the onset, progression, and incidence of ovarian cancer. Additionally, it has been found that immunotherapy, an emerging frontier in tumor treatment, synergizes with ferroptosis in the context of ovarian cancer. Consequently, ferroptosis is likely to become a critical target in the treatment of ovarian cancer.

Current perspectives and trends of CD39-CD73-eAdo/A2aR research in tumor microenvironment: a bibliometric analysis

Background and objectiveExtracellular adenosine (eAdo) bridges tumor metabolism and immune regulation. CD39-CD73-eAdo/A2aR axis regulates tumor microenvironment (TME) and immunotherapy response. In the era of immunotherapy, exploring the impact of the CD39-CD73-eAdo/A2aR axis on TME and developing targeted therapeutic drugs to enhance the efficacy of immunotherapy are the current research hotspots. This study summarizes and explores the research trends and hotspots of the adenosine axis in the field of TME to provide ideas for further in-depth research.MethodsLiterature information was obtained from the Web of Science core collection database. The VOS viewer and the bibliometric tool based on R were used to quantify and identify cooperation information and individual influence by analyzing the detailed information of the global annual publication volume, country/region and institution distribution, article authors and co-cited authors, and journal distribution of these articles. At the same time, the distribution of author keywords and the co-occurrence of author keywords, highly cited articles, and highly co-cited references of CD39-CD73-eAdo/A2aR in the field of TME were analyzed to determine research hotspots and trends.Result1,721 articles published in the past ten years were included in this study. Through bibliometric analysis, we found that (1) 69 countries and regions explored the effect of the CD39-CD73-eAdo/A2aR on TME, and the research was generally on the rise. Researchers in the United States dominated research in this area, with the highest total citation rate. China had the most significant number of publications. (2) Harvard University has published the most articles in this field. (3) 12,065 authors contributed to the publication of papers in this field, of which 23 published at least eight papers. STAGG J had significant academic influence, with 24 published articles and 2,776 citations. Co-cited authors can be clustered into three categories. Stagg J, Allard B, Ohta A, and Antonioli, L occupied a central position in the network. (4) 579 scholarly journals have published articles in this field. The journal FRONTIERS IN IMMUNOLOGY published the most significant number of papers, with 97 articles and a total of 2,317 citations, and the number of publications increased year by year. (5) “The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets” was the most frequently local cited article (163 times). The “A2A adenosine receptor protects tumors from antitumor T cells” was the most co-cited reference (224 times). (6) Through the analysis of author keywords, we found that the relationship between adenosine and immunotherapy was a core concept for many researchers in this field. Breast cancer, melanoma, colorectal cancer, ovarian cancer, glioblastoma, pancreatic cancer, hepatocellular carcinoma, and lung cancer were the most frequent cancer types in adenosine-related tumor studies. Immunotherapy, immunosuppression, immune checkpoint, and immune checkpoint inhibitors were the hot keywords in the research, reflecting the importance of the adenosine metabolic pathway in tumor immunotherapy. The keywords such as Immunogenic cell death, T cells, Sting, regulatory T cells, innate immunity, and immune infiltration demonstrated the pathways by which adenosine affected the TME. The famous author keywords in recent years have been immunotherapy, immunogenic cell death, inflammation, lung cancer, and gastric cancer.ConclusionThe effect of CD39-CD73-eAdo/A2aR on the infiltration and function of various immune cells in TME, tumor immunotherapy response, and patient prognosis has attracted the attention of researchers from many countries/regions. American scholars still dominate the research in this field, but Chinese scholars produce the most research results. The journal FRONTIERS IN IMMUNOLOGY has published the wealthiest research in the field. Stagg J was a highly influential researcher in this field. Further exploration of targeted inhibition of CD39-CD73-eAdo/A2aR alone or in combination with other immunotherapy, radiotherapy, and chemotherapy in treating various cancer types and developing effective clinical therapeutic drugs are continuous research hotspots in this field.

Potentially functional variants of INPP5D and EXOSC3 in immunity B cell-related genes are associated with non-small cell lung cancer survival

B cells are adaptive immune cells in the tumor microenvironment and play an important role in tumor development and metastasis. However, the roles of genetic variants of the immunity B cell-related genes in the survival of patients with non-small cell lung cancer (NSCLC) remain unknown. In the present study, we first evaluated associations between 10,776 single nucleotide polymorphisms (SNPs) in 220 immunity B cell-related genes and survival of NSCLC in a discovery dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that 369 SNPs were significantly associated with overall survival (OS) of NSCLC in multivariable Cox proportional hazards regression analysis (P ≤ 0.05, Bayesian false discovery probability ≤ 0.80), of which 18 SNPs were validated in another independent genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. We then performed linkage disequilibrium (LD) analysis, followed by stepwise analysis with a multivariable Cox regression model. Finally, two independent SNPs, inositol polyphosphate-5-phosphatase D (INPP5D) rs13385922 C>T and exosome component 3 (EXOSC3) rs3208406 A>G, remained significantly associated withNSCLC OS with a combined hazards ratio (HR) of 1.14 (95% confidence interval = 1.06-1.23, P = 2.41×10-4) and 1.20 (95% confidence interval = 1.14-1.28, P = 3.41×10-9), respectively. Furthermore, NSCLC patients with the combination of unfavorable genotypes for these two SNPs were associated with a poor OS (Ptrend = 0.0002) and disease-specific survival (DSS, Ptrend < 0.0001) in the PLCO dataset. Expression quantitative trait loci (eQTL) analysis suggested that the INPP5D rs6782875 T allele was significantly correlated with elevated INPP5D mRNA expression levels in normal lung tissues and whole blood samples, while the EXOSC3 rs3208406 G allele was significantly correlated with increased EXOSC3 mRNA expression levels in normal lung tissues. Our data indicated that genetic variants in these immunity B cell-related genes may predict NSCLC survival possibly by influencing the gene expression.

Single-cell RNA sequencing reveals that MYBL2 in malignant epithelial cells is involved in the development and progression of ovarian cancer

BackgroundOvarian carcinoma (OC) is a prevalent gynecological malignancy associated with high recurrence rates and mortality, often diagnosed at advanced stages. Despite advances in immunotherapy, immune exhaustion remains a significant challenge in achieving optimal tumor control. However, the exploration of intratumoral heterogeneity of malignant epithelial cells and the ovarian cancer tumor microenvironment is still limited, hindering our comprehensive understanding of the disease.Materials and methodsUtilizing single-cell RNA sequencing (scRNA-seq), we comprehensively investigated the cellular composition across six ovarian cancer patients with omental metastasis. Our focus centered on analysis of the malignant epithelial cells. Employing CytoTRACE and slingshot pseudotime analyses, we identified critical subpopulations and explored associated transcription factors (TFs) influencing ovarian cancer progression. Furthermore, by integrating clinical factors from a large cohort of bulk RNA sequencing data, we have established a novel prognostic model to investigate the impact of the tumor immune microenvironment on ovarian cancer patients. Furthermore, we have investigated the condition of immunological exhaustion.ResultsOur study identified a distinct and highly proliferative subgroup of malignant epithelial cells, known as C2 TOP2A+ TCs. This subgroup primarily consisted of patients who hadn’t received neoadjuvant chemotherapy. Ovarian cancer patients with elevated TOP2A expression exhibited heightened sensitivity to neoadjuvant chemotherapy (NACT). Moreover, the transcription factor MYBL2 in this subgroup played a critical role in ovarian cancer development. Additionally, we developed an independent prognostic indicator, the TOP2A TCs Risk Score (TTRS), which revealed a correlation between the High TTRS Group and unfavorable outcomes. Furthermore, immune infiltration and drug sensitivity analyses demonstrated increased responsiveness to Paclitaxel, Cisplatin, and Gemcitabine in the Low TTRS Group.ConclusionThis research deepens our understanding of malignant epithelial cells in ovarian cancer and enhances our knowledge of the ovarian cancer immune microenvironment and immune exhaustion. We have revealed the heightened susceptibility of the C2 TOP2A+ TCs subgroup to neoadjuvant chemotherapy and emphasized the role of MYBL2 within the C2 subgroup in promoting the occurrence and progression of ovarian cancer. These insights provide valuable guidance for the management of ovarian cancer treatment.

The Nectin family ligands, PVRL2 and PVR, in cancer immunology and immunotherapy

In recent years, immunotherapy has emerged as a crucial component of cancer treatment. However, its efficacy remains limited across various cancer types, highlighting unmet needs. Poliovirus receptor-related 2 (PVRL2) and Poliovirus receptor (PVR) are members of the Nectin and Nectin-like Molecules family, known for their role as cell-cell adhesion molecules. With the development of immunotherapy, their involvement in tumor immune mechanisms as immune checkpoint factors has garnered significant attention. PVRL2 and PVR are predominantly expressed on tumor cells and antigen-presenting cells, binding to PVRIG and TIGIT, respectively, which are primarily found on T and NK cells, thereby suppressing antitumor immunity. Notably, gynecological cancers such as ovarian and endometrial cancers exhibit high expression levels of PVRL2 and PVR, with similar trends observed in various other solid and hematologic tumors. Targeting these immune checkpoint pathways offers a promising therapeutic avenue, potentially in combination with existing treatments. However, the immunomodulatory mechanism involving these bindings, known as the DNAM-1 axis, is complex, underscoring the importance of understanding it for developing novel therapies. This article comprehensively reviews the immunomodulatory mechanisms centered on PVRL2 and PVR, elucidating their implications for various cancer types.

Development of ZHPV16E7- granzyme B immunoaffitoxin: dual mechanisms targeting hpv16-positive cervical cancer through epithelial-mesenchymal transition inhibition and cell death

IntroductionCervical cancer, predominantly caused by high-risk human papillomavirus (HPV), remains a major global health challenge. HPV16 is the most prevalent type, and its oncoprotein E7 promotes epithelial-mesenchymal transition (EMT), a critical step in metastasis. Current therapies for HPV16-related cancers are often insufficient, highlighting the need for targeted treatments. We engineered a novel immunotoxin, ZHPV16E7-GrB, by fusing an HPV16E7-specific affibody (ZHPV16E7) with the cytotoxic immune effector granzyme B (GrB). This construct was designed for precise targeting and therapeutic activity against HPV16-positive cervical cancer cells.MethodsZHPV16E7-GrB was engineered, expressed in E. coli, and purified. Binding specificity was assessed via ELISA and immunofluorescence using HPV16-positive (SiHa, CaSki), HPV18-positive (HeLa), and HPV-negative (C33A) cervical cancer cells. Functional assays evaluated cell viability (LDH release, luminescence), migration (Transwell), EMT markers (Western blot for E-cadherin, N-cadherin, Vimentin, Snail), apoptosis (TUNEL, flow cytometry, caspase activation), and pyroptosis (SYTOX Green uptake, cytokine release ELISA, GSDME cleavage). Caspase-3 knockdown and in vitro cleavage assays determined pyroptosis mechanisms.ResultsZHPV16E7-GrB exhibited strong binding specificity for HPV16E7. It significantly inhibited cell growth and suppressed EMT in HPV16-positive cells, evidenced by reduced migration and invasion, downregulation of Vimentin and Snail, increased E-cadherin, and decreased N-cadherin expression. Furthermore, ZHPV16E7-GrB induced apoptosis via caspase-3/caspase-8 activation and triggered pyroptosis through direct cleavage of gasdermin E (GSDME), independent of caspase-3, accompanied by membrane rupture and proinflammatory cytokine release. Crucially, ZHPV16E7-GrB demonstrated selective toxicity, effectively killing HPV16-positive cells while sparing non-HPV16-positive cells, minimizing off-target effects.DiscussionThis study highlights the dual mechanism of ZHPV16E7-GrB, inhibiting EMT and inducing cell death (apoptosis and pyroptosis). These findings demonstrate its significant promise as a targeted therapeutic agent for HPV16-associated cervical cancer, addressing critical unmet needs in current treatment strategies.

Scinderin is a potential prognostic biomarker and correlated with immunological regulation: from pan-cancer analysis to liver hepatocellular carcinoma

AimThis study aimed to systematically dissect the role of Scinderin (SCIN) in tumorigenesis.MethodsBioinformatics techniques were employed based on cancer data from TCGA, ENCORI, HPA, GEPIA2, UALCAN, Kaplan-Meier plotter, TIMER, TISIDB, cBioPortal, HCCDB, GeneMANIA and LinkedOmics database. Experiments in vitro and in vivo were conducted to dissect the role of SCIN in liver hepatocellular carcinoma (LIHC).ResultsSignificantly differential expression of SCIN was found in nine types of cancers, including LIHC. Through pan-cancer analysis, the correlations between SCIN expression with prognosis and immune cell infiltration were proven, especially in LIHC, ovarian serous cystadenocarcinoma and lung adenocarcinoma. The highest frequency of alteration in SCIN (6.81%) was seen in patients with uterine corpus endometrial carcinoma, in which “mutation” was the predominant type, with a frequency of about 5.29%; meanwhile, S673F and S381Y were the two most frequent mutation sites. Furthermore, the abnormal expression of SCIN exhibited a strong relationship with immune cell subtypes, immune checkpoint genes, tumor mutation burden, microsatellite instability, neoantigen, molecular subtypes, mismatch repair signatures and DNA methyl-transferase in different cancer types. Through comparative analysis, we discovered that SCIN was dramatically up-regulated in LIHC, and associated with poor survival. Experiments in vitro and in vivo suggested the knockdown of SCIN could suppress tumor cell proliferation and improve the survival rate partly in animal models.ConclusionThis study reveals SCIN may be a promising biomarker for prognosis and treatment in certain cancers, especially in LIHC.

Case report: Three cases of systemic lupus erythematosus presenting primarily with massive ascites and significantly elevated CA-125 levels and a review of pseudo-pseudo Meigs’ syndrome in literature

This article presents three detailed case reports and a brief review of the literature on a rare manifestation of systemic lupus erythematosus (SLE) known as Pseudo-Pseudo Meigs' Syndrome (PPMS). The patients' condition was characterized by elevated CA-125 levels, massive ascites andpleural effusion which is typically associated with ovarian malignancies but can also present in various non-malignant conditions, including SLE. A thorough literature review was conducted, summarizing similar cases and their clinical outcomes to provide a broader understanding of this uncommon syndrome. The findings emphasize the need for heightened awareness and consideration of pseudo-pseudo Meigs' syndrome in patients with SLE presenting with unexplained ascites and pleural effusion.

Characterization of latently infected EBV+ antibody-secreting B cells isolated from ovarian tumors and malignant ascites

IntroductionIntra-tumoral B cells mediate a plethora of immune effector mechanisms with key roles in anti-tumor immunity and serve as positive prognostic indicators in a variety of solid tumor types, including epithelial ovarian cancer (EOC). Several aspects of intra-tumoral B cells remain unclear, such as their state of activation, antigenic repertoires, and capacity to mature into plasma cells.MethodsB lymphocytes were isolated from primary EOC tissue and malignant ascites and were maintained in cell culture medium. The stably maintained cell lines were profiled with flow cytometry and B cell receptor sequencing. Secreted antibodies were tested with a human proteome array comprising more than 21,000 proteins, followed by ELISA for validation. Originating tumor samples were used for spatial profiling with chip cytometry.ResultsAntibody-secreting B lymphocytes were isolated from the ovarian tumor microenvironment (TME) of four different EOC patients. The highly clonal cell populations underwent spontaneous immortalization in vitro, were stably maintained in an antibody-secreting state, and showed presence of Epstein-Barr viral (EBV) proteins. All originating tumors had high frequency of tumor-infiltrating B cells, present as lymphoid aggregates, or tertiary lymphoid structures. The antigens recognized by three of the four cell lines are coil-coil domain containing protein 155 (CCDC155), growth factor receptor-bound protein 2 (GRB2), and pyruvate dehydrogenase phosphatase2 (PDP2), respectively. Anti-CCDC155 circulating IgG antibodies were detected in 9 of 20 (45%) of EOC patients’ sera. Tissue analyses with multiparameter chip cytometry shows that the antibodies secreted by these novel human B cell lines engage their cognate antigens on tumor cells.DiscussionThese studies demonstrate that within the tumor-infiltrating lymphocyte population in EOC resides a low frequency population of antibody-secreting B cells that have been naturally exposed to EBV. Once stably maintained, these novel cell lines offer unique opportunities for future studies on intratumor B cell biology and new target antigen recognition, and for studies on EBV latency and/or viral reactivation in the TME of non-EBV related solid tumors such as the EOC.

Association of tumor immune infiltration and prognosis with homologous recombination repair genes mutations in early triple-negative breast cancer

The aim of this study was to evaluate the mutation spectrum of homologous recombination repair (HRR) genes and its association with tumor immune infiltration and prognosis in triple-negative breast cancer (TNBC). TNBC patients (434 patients from Ruijin cohort) were evaluated with targeted next-generating sequencing for mutations in HRR genes. The frequencies of mutations were compared with public reference cohorts (320 TNBC patients from METABRIC, 105 from TCGA, and 225 from MSKCC 2018). Associations between mutation status and tumor immune infiltration and prognosis were analyzed. HRR genes mutations were seen in 21.89% patients, with BRCA1/2 mutations significantly enriched in tumors with breast/ovarian cancer family history (P = 0.025) and high Ki-67 levels (P = 0.018). HRR genes mutations were not related with recurrence-free survival (RFS) (adjusted P = 0.070) and overall survival (OS) (adjusted P = 0.318) for TNBC patients, regardless of carboplatin treatment (P > 0.05). Moreover, tumor immune infiltration and PD-L1 expression was positively associated with HRR or BRCA1/2 mutation (all P < 0.001). Patients with both HRR mutation and high CD8+ T cell counts had the best RFS and OS, whereas patients with no HRR mutation and low CD8+ T cell counts had the worst outcomes (RFS P < 0.001, OS P = 0.019). High frequency of HRR gene mutations was found in early TNBC, with no prognostic significance. Immune infiltration and PD-L1 expression was positively associated with HRR mutation, and both HRR mutation and high CD8+ T cell infiltration levels were associated with superior disease outcome.

Integrating single-cell and spatial transcriptomic analysis to unveil heterogeneity in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) presents significant challenges due to its heterogeneity and late-stage diagnoses. Using single-cell and spatial transcriptomics to elucidate the complex landscape of HGSOC to understand its underlying mechanism. Our analysis reveals significant inter- and intra-tumoral diversity, manifested through distinct cellular subpopulations and varied microenvironmental niches. Notably, our findings highlight a widespread immunosuppressive environment, marked by complex networks of cell-cell interactions, particularly evident in areas of elevated tumor cell density within metastatic samples. We identify the exclusive presence of COL14A1+ neoplastic cells in metastatic specimens, alongside a strong correlation between CD8A+ NKT cells and poor prognosis, and elevated CHODL expression in HGSOC metastasis tissues. Furthermore, knockdown experiments targeting CHODL demonstrate its role in reducing migration and invasion abilities in HGSOC cells. A pivotal discovery of our study is the delineation of specific cellular signatures correlated with adverse outcomes, notably a subset of CHODL+ neoplastic cells characterized by a distinct metabolic phenotype with a predilection for lipid metabolism. The therapeutic targeting of this metabolic pathway with existing inhibitors appears promising in curbing tumor proliferation. These findings enhance our understanding of HGSOC heterogeneity and reveal potential therapeutic targets, promising more effective management strategies for this aggressive cancer subtype.

Paraneoplastic neuromyelitis optica spectrum disorder associated with ovarian dysgerminoma: a case report and literature review

Neuromyelitis optica spectrum disorder (NMOSD) is a clinical syndrome characterized by attacks of acute optic neuritis and transverse myelitis. We report a case with paraneoplastic NMOSD that improved after immunosuppressive therapy, surgical resection, and chemotherapy. A 48-year-old woman initially presented with gradual binocular visual loss over the course of one week. The patient was evaluated using magnetic resonance imaging (MRI), computed tomography (CT), visual evoked potential (VEP), pathological biopsy, immunohistochemistry, and autoimmune antibody testing. The brain MRI findings were normal. The VEP revealed prolonged P100 latencies in the right eye and an absence of significant waves in the left eye. Positive serum AQP4-IgG antibodies were found. The patient was diagnosed as NMOSD. Then the patient responded well to treatment with methylprednisolone. An ovarian tumor was found in the patient using abdominal MRI and CT. The tumor was surgically resected, and a pathological biopsy revealed that it was ovarian dysgerminoma. The patient received four rounds of chemotherapy after surgery. One month after the final chemotherapy treatment, a positron emission tomography (PET) scan revealed no tumor. The vision of the patient gradually recovered and serum AQP4 was negative. Furthermore, we summarized the characteristics of patients diagnosed with paraneoplastic NMOSD associated with ovarian neoplasms in previous studies. This is a characteristic case of overlapping NMOSD and ovarian dysgerminoma, demonstrating the importance of tumor therapy in cases of paraneoplastic NMOSD.

Immunoglobulins and serum proteins impair anti-tumor NK cell effector functions in malignant ascites

Introduction Malignant ascites indicates ovarian cancer progression and predicts poor clinical outcome. Various ascites components induce an immunosuppressive crosstalk between tumor and immune cells, which is poorly understood. In our previous study, imbalanced electrolytes, particularly high sodium content in malignant ascites, have been identified as a main immunosuppressive mechanism that impaired NK and T-cell activity. Methods In the present study, we explored the role of high concentrations of ascites proteins and immunoglobulins on antitumoral NK effector functions. To this end, a coculture system consisting of healthy donor NK cells and ovarian cancer cells was used. The anti-EGFR antibody Cetuximab was added to induce antibody-dependent cellular cytotoxicity (ADCC). NK activity was assessed in the presence of different patient ascites samples and immunoglobulins that were isolated from ascites. Results Overall high protein concentration in ascites impaired NK cell degranulation, conjugation to tumor cells, and intracellular calcium signaling. Immunoglobulins isolated from ascites samples competitively interfered with NK ADCC and inhibited the conjugation to target cells. Furthermore, downregulation of regulatory surface markers CD16 and DNAM-1 on NK cells was prevented by ascites-derived immunoglobulins during NK cell activation. Conclusion Our data show that high protein concentrations in biological fluids are able to suppress antitumoral activity of NK cells independent from the mechanism mediated by imbalanced electrolytes. The competitive interference between immunoglobulins of ascites and specific therapeutic antibodies could diminish the efficacy of antibody-based therapies and should be considered in antibody-based immunotherapies.

Editorial: Harnessing tumor microenvironment for gynecologic cancer therapy

Immunosuppressive M2 TAMs represent a promising target population to enhance phagocytosis of ovarian cancer cells in vitro

IntroductionTumor-associated macrophages (TAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype and function of these cells. The present study aims to characterize macrophages in high-grade serous ovarian cancer (HGSOC).MethodsPhenotype and expression of co-regulatory markers were assessed on TAMs derived from malignant ascites (MA) or peripheral blood (PB) by multiparametric flow cytometry. Samples were obtained from HGSOC patients (n=29) and healthy donors (HDs, n=16). Additional expression analysis was performed by RNAseq (n=192). Correlation with clinically relevant parameters was conducted and validated by a second patient cohort (n=517). Finally, the role of TIGIT in repolarization and phagocytosis was investigated in vitro.ResultsExpression of the M2-associated receptors CD163, CD204, and CD206, as well as of the co-regulatory receptors TIGIT, CD226, TIM-3, and LAG-3 was significantly more frequent on macrophages in HGSOC than in HDs. CD39 and CD73 were broadly expressed on (mainly M2) macrophages, but without a clear clustering in HGSOC. CD163 mRNA levels were higher in TAMs from patients with residual tumor mass after surgery and associated with a shorter overall survival. In addition, TIGIT expression was associated with a higher tumor grading, indicating a prognostic relevance of M2 infiltration in HGSOC. TIGIT blockade significantly reduced the frequency of M2 macrophages. Moreover, combined blockade of TIGIT and CD47 significantly increased phagocytosis of ovarian cancer cells by TAMs in comparison to a single blockade of CD47.ConclusionCombined blockade of TIGIT and CD47 represents a promising approach to enhance anti-CD47-facilitated phagocytosis.

Vascular normalization: reshaping the tumor microenvironment and augmenting antitumor immunity for ovarian cancer

Ovarian cancer remains a challenging disease with limited treatment options and poor prognosis. The tumor microenvironment (TME) plays a crucial role in tumor growth, progression, and therapy response. One characteristic feature of the TME is the abnormal tumor vasculature, which is associated with inadequate blood perfusion, hypoxia, and immune evasion. Vascular normalization, a therapeutic strategy aiming to rectify the abnormal tumor vasculature, has emerged as a promising approach to reshape the TME, enhance antitumor immunity, and synergize with immunotherapy in ovarian cancer. This review paper provides a comprehensive overview of vascular normalization and its potential implications in ovarian cancer. In this review, we summarize the intricate interplay between anti-angiogenesis and immune modulation, as well as ICI combined with anti-angiogenesis therapy in ovarian cancer. The compelling evidence discussed in this review contributes to the growing body of knowledge supporting the utilization of combination therapy as a promising treatment paradigm for ovarian cancer, paving the way for further clinical development and optimization of this therapeutic approach.

An exosome-derived lncRNA signature identified by machine learning associated with prognosis and biomarkers for immunotherapy in ovarian cancer

BackgroundOvarian cancer (OC) has the highest mortality rate among gynecological malignancies. Current treatment options are limited and ineffective, prompting the discovery of reliable biomarkers. Exosome lncRNAs, carrying genetic information, are promising new markers. Previous studies only focused on exosome-related genes and employed the Lasso algorithm to construct prediction models, which are not robust.Methods420 OC patients from the TCGA datasets were divided into training and validation datasets. The GSE102037 dataset was used for external validation. LncRNAs associated with exosome-related genes were selected using Pearson analysis. Univariate COX regression analysis was used to filter prognosis-related lncRNAs. The overlapping lncRNAs were identified as candidate lncRNAs for machine learning. Based on 10 machine learning algorithms and 117 algorithm combinations, the optimal predictor combinations were selected according to the C index. The exosome-related LncRNA Signature (ERLS) model was constructed using multivariate COX regression. Based on the median risk score of the training datasets, the patients were divided into high- and low-risk groups. Kaplan-Meier survival analysis, the time-dependent ROC, immune cell infiltration, immunotherapy response, and immune checkpoints were analyzed.Results64 lncRNAs were subjected to a machine-learning process. Based on the stepCox (forward) combined Ridge algorithm, 20 lncRNA were selected to construct the ERLS model. Kaplan-Meier survival analysis showed that the high-risk group had a lower survival rate. The area under the curve (AUC) in predicting OS at 1, 3, and 5 years were 0.758, 0.816, and 0.827 in the entire TCGA cohort. xCell and ssGSEA analysis showed that the low-risk group had higher immune cell infiltration, which may contribute to the activation of cytolytic activity, inflammation promotion, and T-cell co-stimulation pathways. The low-risk group had higher expression levels of PDL1, CTLA4, and higher TMB. The ERLS model can predict response to anti-PD1 and anti-CTLA4 therapy. Patients with low expression of PDL1 or high expression of CTLA4 and low ERLS exhibited significantly better survival prospects, whereas patients with high ERLS and low levels of PDL1 or CTLA4 exhibited the poorest outcomes.ConclusionOur study constructed an ERLS model that can predict prognostic risk and immunotherapy response, optimizing clinical management for OC patients.

Epacadostat stabilizes the apo-form of IDO1 and signals a pro-tumorigenic pathway in human ovarian cancer cells

The tryptophan-degrading enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a plastic immune checkpoint molecule that potently orchestrates immune responses within the tumor microenvironment (TME). As a heme-containing protein, IDO1 catalyzes the conversion of the essential amino acid tryptophan into immunoactive metabolites, called kynurenines. By depleting tryptophan and enriching the TME with kynurenines, IDO1 catalytic activity shapes an immunosuppressive TME. Accordingly, the inducible or constitutive IDO1 expression in cancer correlates with a negative prognosis for patients, representing one of the critical tumor-escape mechanisms. However, clinically trialed IDO1 catalytic inhibitors disappointed the expected anti-tumor efficacy. Interestingly, the non-enzymatic apo-form of IDO1 is still active as a transducing protein, capable of promoting an immunoregulatory phenotype in dendritic cells (DCs) as well as a pro-tumorigenic behavior in murine melanoma. Moreover, the IDO1 catalytic inhibitor epacadostat can induce a tolerogenic phenotype in plasmacytoid DCs, overcoming the catalytic inhibition of IDO1. Based on this recent evidence, IDO1 plasticity was investigated in the human ovarian cancer cell line, SKOV-3, that constitutively expresses IDO1 in a dynamic balance between the holo- and apo-protein, and thus potentially endowed with a dual function (i.e., enzymatic and non-enzymatic). Besides inhibiting the catalytic activity, epacadostat persistently stabilizes the apo-form of IDO1 protein, favoring its tyrosine-phosphorylation and promoting its association with the phosphatase SHP-2. In SKOV-3 cells, both these early molecular events activate a signaling pathway transduced by IDO1 apo-protein, which is independent of its catalytic activity and contributes to the tumorigenic phenotype of SKOV-3 cells. Overall, our findings unveiled a new mechanism of action of epacadostat on IDO1 target, repositioning the catalytic inhibitor as a stabilizer of the apo-form of IDO1, still capable of transducing a pro-tumorigenic pathway in SKOV-3 tumor. This mechanism could contribute to clarify the lack of effectiveness of epacadostat in clinical trials and shed light on innovative immunotherapeutic strategies to tackle IDO1 target.

Platinum desensitization therapy and its impact on the prognosis of ovary high-grade serous adenocarcinoma: a real world-data

BackgroundTo examine the value of five-step platinum desensitization therapy in epithelial ovarian cancerMethodsA retrospective study was conducted on the high-grade serous adenocarcinoma of the ovary (HGSAO) patients who developed a platinum allergy during treatment and received desensitization therapy between January, 2016 and December, 2020. The logistic-regression was adopted to analyze the relationship between platinum desensitization therapy and prognosis in HGSAO patients.Results92 HGSAO patients were included in the study. Among these, 35 patients (38.0%) experienced mild allergic reactions, 51 (55.4%) experienced moderate allergic reactions, and 6 (6.5%) experienced severe allergic reactions. The desensitization therapy was successful in 86 patients (93.5%). Six patients had desensitization failure, of which five experienced severe allergic reactions during desensitization. The logistic-regression analysis revealed no significant correlation between platinum desensitization therapy and progression-free survival (PFS) or overall survival (OS) of patients (P < 0.05). However, the subgroup analysis demonstrated that the success or failure of platinum desensitization therapy significantly impacted the OS of patients who were platinum-sensitive recurrence. The patients who had successful desensitization therapy had a superior OS.ConclusionFive-step platinum desensitization therapy has potential application value in patients who were platinum-sensitive recurrence after first-line treatment but may bear the risk of severe allergic reactions.

The clinical relevance of OSM in inflammatory diseases: a comprehensive review

Oncostatin M (OSM) is a pleiotropic cytokine involved in a variety of inflammatory responses such as wound healing, liver regeneration, and bone remodeling. As a member of the interleukin-6 (IL-6) family of cytokines, OSM binds the shared receptor gp130, recruits either OSMRβ or LIFRβ, and activates a variety of signaling pathways including the JAK/STAT, MAPK, JNK, and PI3K/AKT pathways. Since its discovery in 1986, OSM has been identified as a significant contributor to a multitude of inflammatory diseases, including arthritis, inflammatory bowel disease, lung and skin disease, cardiovascular disease, and most recently, COVID-19. Additionally, OSM has also been extensively studied in the context of several cancer types including breast, cervical, ovarian, testicular, colon and gastrointestinal, brain,lung, skin, as well as other cancers. While OSM has been recognized as a significant contributor for each of these diseases, and studies have shown OSM inhibition is effective at treating or reducing symptoms, very few therapeutics have succeeded into clinical trials, and none have yet been approved by the FDA for treatment. In this review, we outline the role OSM plays in a variety of inflammatory diseases, including cancer, and outline the previous and current strategies for developing an inhibitor for OSM signaling.

Efficacy and safety of immunosuppressive agents for adults with lupus nephritis: a systematic review and network meta-analysis

IntroductionVarious immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN.MethodsWe systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer.ResultsSixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%).DiscussionThis study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.

Obesity modulates the cellular and molecular microenvironment in the peritoneal cavity: implication for ovarian cancer risk

IntroductionAbdominal obesity increases the risk of developing ovarian cancer but the molecular mechanisms of how obesity supports ovarian cancer development remain unknown. Here we investigated the impact of obesity on the immune cell and gene expression profiles of distinct abdominal tissues, focusing on the peritoneal serous fluid (PSF) and the omental fat band (OFB) as critical determinants for the dissemination of ovarian metastases and early metastatic events within the peritoneal cavity.MethodsFemale C57BL/6 mice were fed a low-fat (LFD) or a high-fat diet (HFD) for 12 weeks until the body weights in the HFD group were significantly higher and the mice displayed an impaired glucose tolerance. Then the mice were injected with the murine ovarian cancer cells (MOSE-LTICv) while remaining on their diets. After 21 days, the mice were sacrificed, tumor burden was evaluated and tissues were harvested. The immune cell composition of abdominal tissues and changes in gene expression in the PSF and OFB were evaluated by flow cytometry and qPCR RT2-profiler PCR arrays and confirmed by qRT-PCR, respectively. Other peritoneal adipose tissues including parametrial and retroperitoneal white adipose tissues as well as blood were also investigated.ResultsWhile limited effects were observed in the other peritoneal adipose tissues, feeding mice the HFD led to distinct changes in the immune cell composition in the PSF and the OFB: a depletion of B cells but an increase in myeloid-derived suppressor cells (MDSC) and mono/granulocytes, generating pro-inflammatory environments with increased expression of cyto- and chemokines, and genes supporting adhesion, survival, and growth, as well as suppression of apoptosis. This was associated with a higher peritoneal tumor burden compared to mice fed a LFD. Changes in cellular and genetic profiles were often exacerbated by the HFD. There was a large overlap in genes that were modulated by both the HFD and the cancer cells, suggesting that this ‘genetic fingerprint’ is important for ovarian metastases to the OFB.DiscussionIn accordance with the ‘seed and soil’ theory, our studies show that obesity contributes to the generation of a pro-inflammatory peritoneal environment that supports the survival of disseminating ovarian cancer cells in the PSF and the OFB and enhances the early metastatic adhesion events in the OFB through an increase in extracellular matrix proteins and modulators such as fibronectin 1 and collagen I expression as well as in genes supporting growth and invasion such as Tenacin C. The identified genes could potentially be used as targets for prevention strategies to lower the ovarian cancer risk in women with obesity.

Limitations and potential of immunotherapy in ovarian cancer

Ovarian cancer (OC) is the third most common gynecological cancer and alone has an emergence rate of approximately 308,069 cases worldwide (2020) with dire survival rates. To put it into perspective, the mortality rate of OC is three times higher than that of breast cancer and it is predicted to only increase significantly by 2040. The primary reasons for such a high rate are that the physical symptoms of OC are detectable only during the advanced phase of the disease when resistance to chemotherapies is high and around 80% of the patients that do indeed respond to chemotherapy initially, show a poor prognosis subsequently. This highlights a pressing need to develop new and effective therapies to tackle advanced OC to improve prognosis and patient survival. A major advance in this direction is the emergence of combination immunotherapeutic methods to boost CD8+ T cell function to tackle OC. In this perspective, we discuss our view of the current state of some of the combination immunotherapies in the treatment of advanced OC, their limitations, and potential approaches toward a safer and more effective response.

Ovarian cancer treatment and natural killer cell-based immunotherapy

BackgroundOvarian cancer (OC) is one of the malignant tumors that poses a serious threat to women’s health. Natural killer (NK) cells are an integral part of the immune system and have the ability to kill tumor cells directly or participate indirectly in the anti-tumor immune response. In recent years, NK cell-based immunotherapy for OC has shown remarkable potential. However, its mechanisms and effects remain unclear when compared to standard treatment.MethodsTo explore the value of NK cell-based immunotherapy in the treatment of OC, we conducted a literature review. In comparison to standard treatment, our focus was primarily on the current anti-tumor mechanisms, the clinical effect of NK cells against OC, factors affecting the structure and function of NK cells, and strategies to enhance the effectiveness of NK cells.ResultsWe found that NK cells exert their therapeutic effects in OC through mechanisms such as antibody-dependent cell cytotoxicity, perforin release, and granule enzyme secretion. They also secrete IFN-γ and TNF-α or engage in Fas/FasL and TRAIL/TRAILR pathways, mediating the death of OC cells. In clinical trials, the majority of patients experienced disease stability with mild side effects after receiving NK cell-based immunotherapy, but there is still a lack of high-quality research evidence regarding its clinical effectiveness. OC and prior experience with standard treatments have an effect on NK cells, and it may be considered to maximize NK cell effects through the modulation of the tumor microenvironment or combination with other therapies.ConclusionsIn this review, we have summarized the current evidence of NK cell applications in the treatment of OC. Furthermore, factors and strategies that influence and enhance the role of NK cell immunotherapy are discussed.

NLRC5 overexpression in ovarian tumors remodels the tumor microenvironment and increases T-cell reactivity toward autologous tumor-associated antigens

IntroductionEpithelial ovarian cancer (OC) stands as one of the deadliest gynecologic malignancies, urgently necessitating novel therapeutic strategies. Approximately 60% of ovarian tumors exhibit reduced expression of major histocompatibility complex class I (MHC I), intensifying immune evasion mechanisms and rendering immunotherapies ineffective. NOD-like receptor CARD domain containing 5 (NLRC5) transcriptionally regulates MHC I genes and many antigen presentation machinery components. We therefore explored the therapeutic potential of NLRC5 in OC.MethodsWe generated OC cells overexpressing NLRC5 to rescue MHC I expression and antigen presentation and then assessed their capability to respond to PD-L1 blockade and an infected cell vaccine.ResultsAnalysis of microarray datasets revealed a correlation between elevated NLRC5 expression and extended survival in OC patients; however, NLRC5 was scarcely detected in the OC tumor microenvironment. OC cells overexpressing NLRC5 exhibited slower tumor growth and resulted in higher recruitment of leukocytes in the TME with lower CD4/CD8 T-cell ratios and increased activation of T cells. Immune cells from peripheral blood, spleen, and ascites from these mice displayed heightened activation and interferon-gamma production when exposed to autologous tumor-associated antigens. Finally, as a proof of concept, NLRC5 overexpression within an infected cell vaccine platform enhanced responses and prolonged survival in comparison with control groups when challenged with parental tumors.DiscussionThese findings provide a compelling rationale for utilizing NLRC5 overexpression in “cold” tumor models to enhance tumor susceptibility to T-cell recognition and elimination by boosting the presentation of endogenous tumor antigens. This approach holds promise for improving antitumoral immune responses in OC.

Case report: Interstitial implantation radiotherapy combined with immunotherapy and GM-CSF in oligometastatic platinum-resistant ovarian cancer

BackgroundTreatment for platinum-resistant ovarian cancer is challenging. Currently, platinum-resistant ovarian cancer is typically treated with non-platinum single-agent chemotherapy ± bevacizumab, but the prognosis is often extremely poor. In the treatment of platinum-resistant ovarian cancer patients, reports of triple therapy with interstitial implantation radiotherapy combined with immunotherapy and granulocyte-macrophage colony-stimulating factor (GM-CSF) (PRaG for short) are relatively rare.Case descriptionHere, we report a patient with oligometastatic platinum-resistant ovarian cancer. The patient achieved partial response (PR) of the lesion and sustained benefit for more than six months after receiving interstitial implantation radiotherapy combined with immunotherapy along with GM-CSF.ConclusionThis triple therapy may provide additional options for these patients.

Targeting the immune microenvironment for ovarian cancer therapy

Ovarian cancer (OC) is an aggressive malignancy characterized by a complex immunosuppressive tumor microenvironment (TME). Immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy by reactivating the antitumor immune response suppressed by tumor cells. However, in the case of OC, these inhibitors have failed to demonstrate significant improvements in patient outcomes, and existing biomarkers have not yet identified promising subgroups. Consequently, there remains a pressing need to understand the interplay between OC tumor cells and their surrounding microenvironment to develop effective immunotherapeutic approaches. This review aims to provide an overview of the OC TME and explore its potential as a therapeutic strategy. Tumor-infiltrating lymphocytes (TILs) are major actors in OC TME. Evidence has been accumulating regarding the spontaneous TILS response against OC antigens. Activated T-helpers secrete a wide range of inflammatory cytokines with a supportive action on cytotoxic T-cells. Simultaneously, mature B-cells are recruited and play a significant antitumor role through opsonization of target antigens and T-cell recruitment. Macrophages also form an important subset of innate immunity (M1-macrophages) while participating in the immune-stimulation context. Finally, OC has shown to engage a significant natural-killer-cells immune response, exerting direct cytotoxicity without prior sensitization. Despite this initial cytotoxicity, OC cells develop various strategies to induce an immune-tolerant state. To this end, multiple immunosuppressive molecules are secreted to impair cytotoxic cells, recruit regulatory cells, alter antigen presentation, and effectively evade immune response. Consequently, OC TME is predominantly infiltrated by immunosuppressive cells such as FOXP3+ regulatory T-cells, M2-polarized macrophages and myeloid-derived suppressor cells. Despite this strong immunosuppressive state, PD-1/PD-L1 inhibitors have failed to improve outcomes. Beyond PD-1/PD-L1, OC expresses multiple other immune checkpoints that contribute to immune evasion, and each representing potential immune targets. Novel immunotherapies are attempting to overcome the immunosuppressive state and induce specific immune responses using antibodies adoptive cell therapy or vaccines. Overall, the OC TME presents both opportunities and obstacles. Immunotherapeutic approaches continue to show promise, and next-generation inhibitors offer exciting opportunities. However, tailoring therapies to individual immune characteristics will be critical for the success of these treatments.

CAR-T cell immunotherapy for ovarian cancer: hushing the silent killer

As the most lethal gynecologic oncological indication, carcinoma of the ovary has been ranked as the 5th cause of cancer-related mortality in women, with a high percentage of the patients being diagnosed at late stages of the disease and a five-year survival of ~ 30%. Ovarian cancer patients conventionally undergo surgery for tumor removal followed by platinum- or taxane-based chemotherapy; however, a high percentage of patients experience tumor relapse. Cancer immunotherapy has been regarded as a silver lining in the treatment of patients with various immunological or oncological indications; however, mirvetuximab soravtansine (a folate receptor α-specific mAb) and bevacizumab (a VEGF-A-specific mAb) are the only immunotherapeutics approved for the treatment of ovarian cancer patients. Chimeric antigen receptor T-cell (CAR-T) therapy has achieved tremendous clinical success in the treatment of patients with certain B-cell lymphomas and leukemias, as well as multiple myeloma. In the context of solid tumors, CAR-T therapies face serious obstacles that limit their therapeutic benefit. Such hindrances include the immunosuppressive nature of solid tumors, impaired tumor infiltration, lack of qualified tumor-associated antigens, and compromised stimulation and persistence of CAR-Ts following administration. Over the past years, researchers have made arduous attempts to apply CAR-T therapy to ovarian cancer. In this review, we outline the principles of CAR-T therapy and then highlight its limitations in the context of solid tumors. Ultimately, we focus on preclinical and clinical findings achieved in CAR-T-mediated targeting of different ovarian cancer-associated target antigens.

Deciphering the puzzle: a case report of Tjalma syndrome (pseudo-pseudo Meigs' syndrome) with profoundly elevated CA-125 and pleural effusion

Elevated CA-125 levels, polyserous effusions (such as pleural effusion, ascites, etc.) in young women with systemic lupus erythematosus (SLE) may signal pseudo-pseudo Meigs’ syndrome (PPMS), after excluding other causes. We describe a 32-year-old SLE patient with recurrent bilateral pleural effusions and unexplained hypercalcemia for 10 months. Extensive evaluations revealed no infections or tumors. Cytokine analysis showed elevated interleukin (IL) levels, especially IL-6 in pleural effusion. Treatment with immunosuppressive therapy resulted in reduced cancer antigen (CA) 125 levels and decreased effusion volume, demonstrating a positive response to intervention in this case of PPMS.

Multifactor assessment of ovarian cancer reveals immunologically interpretable molecular subtypes with distinct prognoses

BackgroundOvarian cancer (OC) is a highly heterogeneous and malignant gynecological cancer, thereby leading to poor clinical outcomes. The study aims to identify and characterize clinically relevant subtypes in OC and develop a diagnostic model that can precisely stratify OC patients, providing more diagnostic clues for OC patients to access focused therapeutic and preventative strategies.MethodsGene expression datasets of OC were retrieved from TCGA and GEO databases. To evaluate immune cell infiltration, the ESTIMATE algorithm was applied. A univariate Cox analysis and the two-sided log-rank test were used to screen OC risk factors. We adopted the ConsensusClusterPlus algorithm to determine OC subtypes. Enrichment analysis based on KEGG and GO was performed to determine enriched pathways of signature genes for each subtype. The machine learning algorithm, support vector machine (SVM) was used to select the feature gene and develop a diagnostic model. A ROC curve was depicted to evaluate the model performance.ResultsA total of 1,273 survival-related genes (SRGs) were firstly determined and used to clarify OC samples into different subtypes based on their different molecular pattern. SRGs were successfully stratified in OC patients into three robust subtypes, designated S-I (Immunoreactive and DNA Damage repair), S-II (Mixed), and S-III (Proliferative and Invasive). S-I had more favorable OS and DFS, whereas S-III had the worst prognosis and was enriched with OC patients at advanced stages. Meanwhile, comprehensive functional analysis highlighted differences in biological pathways: genes associated with immune function and DNA damage repair including CXCL9, CXCL10, CXCL11, APEX, APEX2, and RBX1 were enriched in S-I; S-II combined multiple gene signatures including genes associated with metabolism and transcription; and the gene signature of S-III was extensively involved in pathways reflecting malignancies, including many core kinases and transcription factors involved in cancer such as CDK6, ERBB2, JAK1, DAPK1, FOXO1, and RXRA. The SVM model showed superior diagnostic performance with AUC values of 0.922 and 0.901, respectively. Furthermore, a new dataset of the independent cohort could be automatically analyzed by this innovative pipeline and yield similar results.ConclusionThis study exploited an innovative approach to construct previously unexplored robust subtypes significantly related to different clinical and molecular features for OC and a diagnostic model using SVM to aid in clinical diagnosis and treatment. This investigation also illustrated the importance of targeting innate immune suppression together with DNA damage in OC, offering novel insights for further experimental exploration and clinical trial.

CD44v6 specific CAR-NK cells for targeted immunotherapy of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a major challenge for current therapies. CAR-T cells have shown promising results in blood cancers, however, their effectiveness against solid tumors remains a hurdle. Recently, CD44v6-directed CAR-T cells demonstrated efficacy in controlling tumor growth in multiple myeloma and solid tumors such as HNSCC, lung and ovarian adenocarcinomas. Apart from CAR-T cells, CAR-NK cells offer a safe and allogenic alternative to autologous CAR-T cell therapy. In this paper, we investigated the capacity of CAR-NK cells redirected against CD44v6 to execute cytotoxicity against HNSCC. Anti-CD44v6 CAR-NK cells were generated from healthy donor peripheral blood-derived NK cells using gamma retroviral vectors (gRVs). The NK cell transduction was optimized by exploring virus envelope proteins derived from the baboon endogenous virus envelope (BaEV), feline leukemia virus (FeLV, termed RD114-TR) and gibbon ape leukemia virus (GaLV), respectively. BaEV pseudotyped gRVs induced the highest transduction rate compared to RD114-TR and GaLV envelopes as measured by EGFP and surface CAR expression of transduced NK cells. CAR-NK cells showed a two- to threefold increase in killing efficacy against various HNSCC cell lines compared to unmodified, cytokine-expanded primary NK cells. Anti-CD44v6 CAR-NK cells were effective in eliminating tumor cell lines with high and low CD44v6 expression levels. Overall, the improved cytotoxicity of CAR-NK cells holds promise for a therapeutic option for the treatment of HNSCC. However, further preclinical trials are necessary to test in vivo efficacy and safety, as well to optimize the treatment regimen of anti-CD44v6 CAR-NK cells against solid tumors.

ISG20 stimulates anti-tumor immunity via a double-stranded RNA-induced interferon response in ovarian cancer

Augmentation of endogenous double-stranded RNA (dsRNA) has become a promising strategy for activating anti-tumor immunity through induction of type I interferon (IFN) in the treatment of ovarian carcinoma. However, the underlying regulatory mechanisms of dsRNA in ovarian carcinoma remain elusive. From The Cancer Genome Atlas (TCGA), we downloaded RNA expression profiles and clinical data of patients with ovarian carcinoma. Using the consensus clustering method, patients can be classified by their expression level of core interferon-stimulated genes (ISGs): IFN signatures high and IFN signatures low. The IFN signatures high group had a good prognosis. Gene set enrichment analysis (GSEA) showed that differentially expressed genes (DEGs) were primarily associated with anti-foreign immune responses. Based on results from protein-protein interaction (PPI) networks and survival analysis, ISG20 was identified as a key gene involved in host anti-tumor immune response. Further, elevated ISG20 expression in ovarian cancer cells led to increased IFN-β production. The elevated interferon improved the immunogenicity of tumor cells and generated chemokines that attract immune cells to infiltrate the area. Upon overexpression of ISG20, endogenous dsRNA accumulated in the cell and stimulated IFN-β production through the Retinoic acid-inducible gene I (RIG-I)-mediated dsRNA sense pathway. The accumulation of dsRNA was associated with the ribonuclease activity of ISG20. This study suggests that targeting ISG20 is a potential immune therapeutic approach to treat ovarian cancer.

Unveiling the novel immune and molecular signatures of ovarian cancer: insights and innovations from single-cell sequencing

Ovarian cancer is a highly heterogeneous and lethal malignancy with limited treatment options. Over the past decade, single-cell sequencing has emerged as an advanced biological technology capable of decoding the landscape of ovarian cancer at the single-cell resolution. It operates at the level of genes, transcriptomes, proteins, epigenomes, and metabolisms, providing detailed information that is distinct from bulk sequencing methods, which only offer average data for specific lesions. Single-cell sequencing technology provides detailed insights into the immune and molecular mechanisms underlying tumor occurrence, development, drug resistance, and immune escape. These insights can guide the development of innovative diagnostic markers, therapeutic strategies, and prognostic indicators. Overall, this review provides a comprehensive summary of the diverse applications of single-cell sequencing in ovarian cancer. It encompasses the identification and characterization of novel cell subpopulations, the elucidation of tumor heterogeneity, the investigation of the tumor microenvironment, the analysis of mechanisms underlying metastasis, and the integration of innovative approaches such as organoid models and multi-omics analysis.

Integrated machine learning identifies a cellular senescence-related prognostic model to improve outcomes in uterine corpus endometrial carcinoma

BackgroundUterine Corpus Endometrial Carcinoma (UCEC) stands as one of the prevalent malignancies impacting women globally. Given its heterogeneous nature, personalized therapeutic approaches are increasingly significant for optimizing patient outcomes. This study investigated the prognostic potential of cellular senescence genes(CSGs) in UCEC, utilizing machine learning techniques integrated with large-scale genomic data.MethodsA comprehensive analysis was conducted using transcriptomic and clinical data from 579 endometrial cancer patients sourced from the Cancer Genome Atlas (TCGA). A subset of 503 CSGs was assessed through weighted gene co-expression network analysis (WGCNA) alongside machine learning algorithms, including Gaussian Mixture Model (GMM), support vector machine - recursive feature elimination (SVM-RFE), Random Forest, and eXtreme Gradient Boosting (XGBoost), to identify key differentially expressed cellular senescence genes. These genes underwent further analysis to construct a prognostic model.ResultsOur analysis revealed two distinct molecular clusters of UCEC with significant differences in tumor microenvironment and survival outcomes. Utilizing cellular senescence genes, a prognostic model effectively stratified patients into high-risk and low-risk categories. Patients in the high-risk group exhibited compromised overall survival and presented distinct molecular and immune profiles indicative of tumor progression. Crucially, the prognostic model demonstrated robust predictive performance and underwent validation in an independent patient cohort.ConclusionThe study emphasized the significance of cellular senescence genes in UCEC progression and underscored the efficacy of machine learning in developing reliable prognostic models. Our findings suggested that targeting cellular senescence holds promise as a strategy in personalized UCEC treatment, thus warranting further clinical investigation.

Impact of programmed cell death protein 1 inhibitor therapy on the survival of patients with advanced or recurrent uterine cancers: a meta-analysis

IntroductionNo prior meta-analysis has investigated the impact of programmed cell death protein 1 (PD-1) inhibitor therapy on survival outcomes in patients with advanced or recurrent uterine cancers (including both corpus and cervical cancers).MethodsA comprehensive search of PubMed and Embase databases was conducted, covering the past 10 years (up to August 2023) and encompassing all clinical research related to uterine cancer. Five randomized controlled trials and one cohort study met the inclusion criteria and were included in the meta-analysis. Data on patient demographics, clinical characteristics, treatment regimens, and survival outcomes were extracted. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), as well as the relative risk of grade 3 or higher adverse events, were pooled using random-effects models.ResultsPatients receiving PD-1 inhibitors had better OS (HR, 0.65, 95% CI, 0.59–0.72; P<.001) and PFS (HR, 0.59, 95% CI, 0.49–0.70; P<.001) than those receiving variable non-PD-1 inhibitor therapies among 3452 uterine cancer patients. The leave-one-out meta-analysis of the HR of OS showed no individual study impact on the estimation of the overall effect size. Subgroup analysis revealed better OS in the PD-1 inhibitors use than the controls in cervical cancer (HR, 0.68, 95% CI, 0.59–0.79), endometrial cancer (HR, 0.62, 95% CI, 0.54-0.72), and pembrolizumab use (HR, 0.66, 95% CI, 0.57–0.75) subgroups. Patients with advanced cervical cancer, who had CPS > 1, receiving PD-1 inhibitors have statistically significant benefits in OS compared to controls (HR, 0.65, 95% CI, 0.53-0.80). The pooled HR for overall survival was 0.71 (95% CI, 0.60-0.82; P<.001) in patients who received PD-1 inhibitors as compared to those who did not receive PD-1 inhibitors in proficient mismatch repair (MMR) endometrial cancer patients. However, in deficient MMR patients, the HR was 0.30 (95% CI, 0.13-0.70). The relative risk of grade 3 or higher adverse events was not higher in the PD-1 inhibitor group (relative risk, 1.12, 95% CI, 0.98–1.27).ConclusionSurvival was significantly better using PD-1 inhibitor therapy than variable non-PD-1 inhibitor chemotherapies among patients with advanced or recurrent uterine cancers.

Dendritic cell vaccination combined with carboplatin/paclitaxel for metastatic endometrial cancer patients: results of a phase I/II trial

BackgroundMetastatic endometrial cancer (mEC) continues to have a poor prognosis despite the introduction of several novel therapies including immune checkpoints inhibitors. Dendritic cell (DC) vaccination is known to be a safe immunotherapeutic modality that can induce immunological and clinical responses in patients with solid tumors. Platinum-based chemotherapy is known to act synergistically with immunotherapy by selectively depleting suppressive immune cells. Therefore, we investigated the immunological efficacy of combined chemoimmunotherapy with an autologous DC vaccine and carboplatin/paclitaxel chemotherapy.Study designThis is a prospective, exploratory, single-arm phase I/II study (NCT04212377) in 7 patients with mEC. The DC vaccine consisted of blood-derived conventional and plasmacytoid dendritic cells, loaded with known mEC antigens Mucin-1 and Survivin. Chemotherapy consisted of carboplatin/paclitaxel, given weekly for 6 cycles and three-weekly for 3 cycles. The primary endpoint was immunological vaccine efficacy; secondary endpoints were safety and feasibility.ResultsProduction of DC vaccines was successful in five out of seven patients. These five patients started study treatment and all were able to complete the entire treatment schedule. Antigen-specific responses could be demonstrated in two of the five patients who were treated. All patients had at least one adverse event grade 3 or higher. Treatment-related adverse events grade ≥3 were related to chemotherapy rather than DC vaccination; neutropenia was most common. Suppressive myeloid cells were selectively depleted in peripheral blood after chemotherapy.ConclusionDC vaccination can be safely combined with carboplatin/paclitaxel in patients with metastatic endometrial cancer and induces antigen-specific responses in a minority of patients. Longitudinal immunological phenotyping is suggestive of a synergistic effect of the combination.

Mismatch repair gene MSH6 correlates with the prognosis, immune status and immune checkpoint inhibitors response of endometrial cancer

ObjectiveMany patients treated with immune checkpoint inhibitors (ICIs) developed primary or secondary drug resistance for unknown reasons. This study investigates whether mismatch repair (MMR) genes are responsible for this therapeutic restriction.MethodsWe obtained the transcriptional, clinical and single nucleotide polymorphism data for endometrial cancer (EC) from The Cancer Genome Atlas and the immunophenoscore data of EC from The Cancer Immunome Atlas, then analyzed in R to evaluate the relationship between MMR genes and clinicopathological features, prognosis, immune infiltration, immune checkpoint expression and responsiveness to ICIs in EC. We used differentially expressed genes in the MSH6 high and low expression groups to conduct GO and KEGG analyses to explore the impact of MSH6 on the biological functions of EC. Finally, we verified the bioinformatics results with in vitro experiments.ResultsOur analyses showed that compared with the high MSH6 expression group, the low MSH6 expression group had better survival outcomes and less aggressive clinicopathological features. In the multivariate Cox analysis, MSH6 was the only independent risk factor that could predict the prognosis of EC. Besides, the low MSH6 expression group also had a higher immune score, more active immune infiltration and higher immune checkpoint expression, resulting in better responsiveness to ICIs treatment, consistent with the enrichment of GO terms and KEGG pathways related to immune response in this group. Meanwhile, the GO and KEGG enrichment results of the MSH6 high expression group were associated with cell cycle, DNA damage repair and tumorigenesis. To exclude the influence of MSH6 mutations, we performed the previous analyses on the MSH6 wild-type tumor samples and obtained consistent results. In vitro experiments also confirmed that after knocking down MSH6 in endometrial cancer cells, their proliferation, migration and invasion abilities were weakened, while the expression levels of PD-L1 and PD-L2 were elevated. In comparison, overexpression of MSH6 showed an opposite trend.ConclusionReduced MSH6 expression could serve as a potential biomarker for predicting better prognosis, active immune status, higher immune checkpoint expression level and better responsiveness to ICIs treatment in EC. MSH6 may become a potential target for treating solid tumors.

Immunotherapy in endometrial cancer: mechanisms, clinical evidence, and future directions

Endometrial cancer (EC) treatment has been revolutionized by the integration of immunotherapy, particularly for molecularly defined subsets of patients. The classification of EC into DNA polymerase epsilon-mutated (POLE-mutant), mismatch repair-deficient (dMMR), p53-abnormal, and no specific molecular profile (NSMP) subtypes provides a critical framework for predicting response to immune checkpoint blockade. dMMR and POLE-mutant tumors, with their hypermutated and immunogenic phenotypes, demonstrate exceptional sensitivity to Programmed Death-1(PD-1) inhibitors such as pembrolizumab and dostarlimab in clinical trials. In contrast, overcoming the immunoresistant nature of NSMP and p53-abnormal EC requires innovative combinations, exemplified by the success of pembrolizumab plus the multitargeted tyrosine kinase inhibitor lenvatinib. Recent practice-changing clinical trials have further established combination strategies incorporating PD-1 blockade with chemotherapy as a new first-line standard for advanced disease, marking a paradigm shift in the management of advanced EC. This review synthesizes the mechanistic basis for these approaches, the compelling clinical evidence supporting approved therapies, and the frontier of investigational strategies, including cellular therapies, novel immune checkpoints, and rational combination regimens—aimed at expanding the benefit of immunotherapy to a broader range of patients with EC.

Neutrophil extracellular traps in tumor progression of gynecologic cancers

This article delves into the intricate interplay between tumors, particularly gynecologic malignancies, and neutrophil extracellular traps (NETs). The relationship between tumors, specifically gynecologic malignancies, and NETs is a multifaceted and pivotal area of study. Neutrophils, pivotal components of the immune system, are tasked with combating foreign invaders. NETs, intricate structures released by neutrophils, play a vital role in combating systemic infections but also play a role in non-infectious conditions such as inflammation, autoimmune diseases, and cancer. Cancer cells have the ability to attract neutrophils, creating tumor-associated neutrophils, which then stimulate the release of NETs into the tumor microenvironment. The impact of NETs within the tumor microenvironment is profound and intricate. They play a significant role in influencing cancer development and metastasis, as well as modulating tumor immune responses. Through the release of proteases and pro-inflammatory cytokines, NETs directly alter the behavior of tumor cells, increasing invasiveness and metastatic potential. Additionally, NETs can trigger epithelial-mesenchymal transition in tumor cells, a process associated with increased invasion and metastasis. The interaction between tumors and NETs is particularly critical in gynecologic malignancies such as ovarian, cervical, and endometrial cancer. Understanding the mechanisms through which NETs operate in these tumors can offer valuable insights for the development of targeted therapeutic interventions. Researchers are actively working towards harnessing this interaction to impede tumor progression and metastasis, opening up new avenues for future treatment modalities. As our understanding of the interplay between tumors and NETs deepens, it is anticipated that novel treatment strategies will emerge, potentially leading to improved outcomes for patients with gynecologic malignancies. This article provides a comprehensive overview of the latest research findings on the interaction between NETs and cancer, particularly in gynecologic tumors, serving as a valuable resource for future exploration in this field.

Efficacy and safety of PARP inhibitors in advanced or recurrent endometrial cancer: a systematic review and meta-analysis

Objective Several clinical trials have explored the efficacy and safety of Poly (ADP-ribose) polymerase (PARP) inhibitors in endometrial cancer (EC). However, evidence supporting PARP inhibitors alone or in combination with other medications in advanced or recurrent EC remains limited. Methods We utilized Cochrane Library, PubMed, Web of Science, and Embase to identify clinical trials that evaluated the efficacy and safety of PARP inhibitors in advanced and recurrent EC. The outcomes analyzed included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events (AEs). We computed hazard ratios (HRs) for PFS and OS, with 95% confidence intervals (CIs) from randomized trials. Subgroup analysis was conducted based on the PARP inhibitor combination therapy strategies (with antiprogrammed death 1 [PD-1]/antiprogrammed death ligand-1 [PD-L1] inhibitors or antiangiogenic agents). Results Overall, 12 clinical trials for a total number of 1,594 patients diagnosed with advanced or recurrent EC were included in this meta-analysis. The duration of follow-up time ranged from a median of 7.4 to 31.9 months, and the pooled median PFS was 6.43 months. The results showed that the combination of PARP with PD-L1/PD-1 inhibitors could significantly prolong PFS versus placebo (hazard ratio [HR] = 0.567; 95% confidence interval [CI] = 0.469–0.686; p < 0.05). Based on the subgroup analysis, the pooled median PFS was found to be 7.59 months for the combination of PARP with PD-L1/PD-1 inhibitors. In addition, the pooled median PFS at 6 months was 0.44 based on the analysis of four included studies. In the intention-to-treat population, there was no PFS/OS difference between PARP inhibitor monotherapy and placebo (PFS: HR = 0.684 [95% CI = 0.334–1.398], p > 0.05; OS: HR = 0.787 [95% CI = 0.279–2.219], p > 0.05). The ORR was notably elevated in the combined therapy group compared with PARP inhibitor monotherapy (OR = 3.34 [95% CI = 1.095–10.165], p = 0.034). The most common AEs included fatigue (226, 54.5%), nausea (219, 52.8%), anemia (219, 52.8%), diarrhea (127, 30.6%), and alopecia (121, 29.2%). Conclusion The combination of a PARP inhibitor with a PD-L1/PD-1 inhibitor shows modest activity with substantial toxicity, particularly in heavily pretreated and largely pMMR populations. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD42024556356.

The prognostic significance of JAML and its role in remodeling the immune microenvironment via the cGAS-STING pathway in endometrial cancer

Background Endometrial cancer (EC) is a major gynecological malignancy with a poor prognosis in the advanced stages. Junctional adhesion molecule-like protein (JAML) is gaining attention in cancer biology; however, its role in EC remains unclear. Methods This study integrated multi-omics data (TCGA, pan-cancer analysis and single-cell transcriptomics), dual independent clinical cohorts (TCGA dataset and an institutional cohort), and in vitro / in vivo experimental models to systematically analyze JAML expression patterns, clinical relevance, and tumor-progression regulatory mechanisms in EC. Experimental approaches included: immunohistochemistry (IHC), qRT-PCR, and Western blotting for expression validation; shRNA knockdown, Transwell/scratch assays, CCK-8 assays, and conditioned medium co-culture models for functional analysis; bioinformatics tools (ESTIMATE, TIMER, MCP-counter) and flow cytometry for immune microenvironment evaluation; drug sensitivity analysis (Genomics of Drug Sensitivity in Cancer (GDSC)/Tumor Immune Dysfunction and Exclusion (TIDE) databases) and prognostic modeling (Cox regression/nomogram) for clinical application assessment. Results In EC, JAML expression was significantly downregulated and correlated with poor prognosis. JAML knockdown promoted cancer cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) (all P < 0.01), accompanied by reduced stimulator of interferon genes (STING) phosphorylation (P < 0.01). Low JAML expression correlated with decreased M1 (CD86 + , P < 0.01) and increased M2 (CD206 + , P < 0.01) macrophage infiltration. It was also linked to reduced cisplatin/paclitaxel sensitivity (P < 0.05) and lower immunotherapy response (29.04% vs. 45.05%, P = 0.015). STING agonist cyclic GMP–AMP (cGAMP) partially restored M1 infiltration and chemosensitivity after JAML knockdown in vitro . A nomogram incorporating JAML and clinicopathological parameters showed improved predictive performance (AUC 0.885; cutoff 0.882; sensitivity 0.818, specificity 0.820), with calibration curves confirming good agreement between predicted and observed recurrence. Conclusions These findings suggest that JAML deficiency may suppress cyclic GMP-AMP synthase (cGAS)-STING pathway activation, potentially contributing to M1/M2 macrophage polarization imbalance and facilitating EC progression. Clinically, JAML expression shows promise as a potential biomarker for prognostic stratification and treatment response prediction (chemotherapy/immunotherapy), providing insights for developing precision immunochemotherapy strategies in EC.

Unveiling trends and clinical progress of immunotherapy for endometrial cancer: a scientometric and clinical trial landscape analysis

Background Endometrial cancer (EC) is a heterogeneous and increasingly prevalent malignancy characterized by distinct molecular subgroups that exhibit fundamentally different immune profiles. These immunologic differences shape tumor–immune interactions, influence responsiveness to immunotherapy, and underscore the importance of biologically informed treatment strategies. As the clinical application of immune checkpoint inhibitors expands, understanding the mechanistic and translational landscape of immunotherapy in EC has become essential for guiding precision oncology. Methods We systematically retrieved 836 immunotherapy-related publications on EC from the Web of Science Core Collection (1999–2024) and conducted a scientometric analysis using VOSviewer and CiteSpace. Analyses included publication trends, country and institutional collaborations, author networks, and keyword clustering. Furthermore, we screened 391 clinical trials from ClinicalTrials.gov and ICTRP databases to assess the clinical research landscape. Results Publication output and clinical trials on EC immunotherapy have shown a continuous upward trend over the past two decades. The United States and China emerged as leading contributors in both publications and pivotal clinical trials. Among the most frequently co-cited references, clinical studies account for a significant proportion, particularly those published in the last five years. The landscape reflects a shift toward immune checkpoint blockade and combination therapy strategies, with some clinical trials demonstrating promising efficacy. Conclusion Our integrated scientometric and clinical trial analysis reveals a rapid evolution in EC immunotherapy research, highlighting checkpoint blockade as a central therapeutic approach. The trend toward combination regimens underscores the translational potential of immunotherapy in EC and points toward emerging directions for future research and clinical application.

Genomic and immunological differences in endometrial cancer: a comparative study between young and old Asian patients

Background Endometrial carcinoma (EC) demonstrates a pronounced age-related disparity in clinical outcomes, yet the underlying genomic and molecular mechanisms remain incompletely characterized, especially across Asian populations. Methods We performed an integrated genomic analysis of two independent cohorts: the MSK-MET Asian cohort (n=94) and a Chinese EC cohort, EC-3rd-SYSU (n=18). Patients were stratified by age (young, ≤50 years; old, >50 years). We compared mutation spectra, pathway enrichment, tumor mutation burden (TMB), microsatellite instability (MSI), and survival outcomes between age groups. Results Across both cohorts, PTEN, PIK3CA, and ARID1A were the most frequently mutated genes, forming a conserved oncogenic core centered on PI3K/AKT signaling and chromatin remodeling. Younger patients showed enrichment of CTNNB1 and PTEN mutations, while older patients exhibited higher frequencies of TP53, ARID1A, and MSH6 alterations. Younger tumors were characterized by activation of stemness and metabolic signaling pathways, whereas older tumors were enriched in cellular senescence, endocrine resistance, and longevity regulation pathways. No significant age-associated differences were observed in TMB or MSI status. The Chinese cohort had higher mutation rates of PTEN, KRAS, and FGFR2, while TP53 and PIK3R1 mutations were more frequent in the MSK-MET cohort. These age-specific molecular subtypes correlated with significant survival differences. Conclusions Our study identifies conserved age-specific molecular subtypes of EC and reveals population-specific genomic features, underscoring the need for age-tailored and ethnicity-aware therapeutic strategies.

Inflammation-driven mechanisms in endometrial cancer: pathways from inflammatory microenvironment remodeling to immune escape

The progression of endometrial cancer (EC) is significantly affected by the inflammatory microenvironment (IME), which is essential for facilitating immune evasion and developing resistance to therapeutic interventions. Components that promote immune suppression, such as regulatory T cells (Tregs), macrophages associated with tumors (TAMs), cytokines like interleukin-10 (IL-10) and transforming growth factors-beta (TGF-β), are crucial in establishing a favorable microenvironment for tumor growth. TAMs with a M2-like phenotype promote angiogenesis and inhibit antitumor immunity through the secretion pro-tumorigenic factor. Further, metabolic shifts in the extracellular matrix and structural modifications of the extracellular matrix (ECM) inhibit the infiltration of cytotoxic T lymphocytes (CTLs), thereby strengthening mechanisms of immune evasion. Inflammatory signaling pathways, such as interleukin-6/janus kinase/signal transducer and activator of transcription 3 (IL-6/JAK/STAT3) and NF-κB/tumor necrosis factor-alpha (TNF-α/NF-κB), also stimulate the expression immune checkpoint molecules, such as programmed cell death protein 1 (PD-1). Novel interventions aimed at modulating immune checkpoints, inhibiting TGF-β signaling, and altering metabolic circuits are under investigation and offer potential to counteract immune suppression and enhance therapeutic success. Nevertheless, significant obstacles remain, including intratumoral heterogeneity, fluctuating immune dynamics, and the absence of dependable biomarkers. Advancements in single-cell analysis and spatial transcriptomics are anticipated to unveil actionable molecular patterns and support the development of individualized strategies to interrupt immune evasion and therapeutic resistance in EC. These advances offer promise for personalized immunotherapy approaches that could significantly improve outcomes in endometrial cancer patients.

Pan-cancer multi-omics characterization of calcyphosine and its revealed links to the immune microenvironment and regulatory networks in endometrial carcinoma

Objective The calcium-dependent activator protein for secretion (CAPS) has emerged as a protein of interest in tumor biology; however, its functional significance in endometrial carcinoma (EC) remains largely unexplored. Methods We performed an integrative analysis leveraging bulk RNA sequencing data from The Cancer Genome Atlas, GTEx, and publicly available EC datasets, coupled with gene set enrichment analysis (GSEA) and single-cell transcriptomic profiling. The association between CAPS expression and clinicopathological parameters as well as patient prognosis was systematically assessed. In addition, functional enrichment, intercellular communication, and immune infiltration analyses were conducted to elucidate the molecular and microenvironmental roles of CAPS. In vitro assays were employed to validate the biological effects of CAPS knockdown on EC cell proliferation, migration, and invasion. Results CAPS was significantly upregulated in early-stage, low-grade, and endometrioid endometrial carcinoma, and its elevated expression was associated with improved patient survival. GSEA indicated that high CAPS expression was correlated with enhanced ribosome biogenesis and oxidative phosphorylation, along with suppression of proliferative signaling, reflecting a metabolically differentiated phenotype. Single-cell transcriptomic analysis revealed that CAPS was specifically enriched in terminally differentiated secretory epithelial cells, promoting epithelial maturation and oxidative metabolism. Furthermore, CAPS-positive cells exhibited extensive crosstalk with immune cells, suggesting a potential role in facilitating anti-tumor immune responses. Functional assays confirmed that CAPS knockdown markedly enhanced EC cell proliferation, migration, and invasion. Conclusion CAPS may act as a tumor suppressor in EC by stabilizing microtubule architecture, reprogramming cellular metabolism, and modulating immune interactions within the tumor microenvironment. These findings highlight CAPS as a promising prognostic biomarker and potential therapeutic target in EC.

Evaluation of microsatellite instability patterns in mismatch repair deficiency: a retrospective analysis of 285 endometrial cancers

ObjectiveIn this study, we systematically compared the microsatellite shift patterns detected by PCR-based microsatellite instability analysis (PCR-MSI) in mismatch repair (MMR)-deficient ECs and analyzed the clinicopathological features associated with minimal versus major shifts.MethodWe evaluated the microsatellite shift patterns using five NCI-recommended loci in 285 MMR-deficient ECs identified through immunohistochemistry (IHC). A minimal shift was defined as a one-to-three nucleotide repeat shift observed at least at one locus. Then, clinicopathological characteristics were analyzed for two distinct groups: the minimal shift group and the major shift group. Finally, further analysis of MMR/MSI discordant cases was performed through MLH1 promoter methylation detection and MMR gene germline mutation detection.ResultOf the 285 MMR-deficiency ECs, 169 (59.3%) had combined loss of MLH1 and PMS2, 54 (18.9%) had combined loss of MSH2 and MSH6, 39 (13.7%) had isolated loss of MSH6 and 23 (8.1%) had isolated loss of PMS2 by IHC. The rate of inconsistency between MMR-IHC and PCR-MSI was 12.3% (35/285). However, based on the minimal shifting criteria, 13 cases with MSI-L were reassessed as MSI-H because of the occurrence of minimal microsatellite shifts, and the inconsistency rate between MMR-IHC and MSI-PCR decreased to 7.7% (22/285). Additionally, discordant cases showed a higher frequency (91%, 20/22 cases) of minimal shift involving the mononucleotide locus. Among the 7 MLH1/PMS2-deficient cases, 3 were successfully detected and showed MLH1 promoter methylation. A total of 13 of 22 patients were successfully completed MMR gene germline testing, 11 cases had germline mutations in MSH6 and 3 cases harbored frameshift deletions (p.F1088Lfs*). Overall, the frequency of minimal shift was 100% (39/39) at isolated loss of MSH6, 85.8% (145/169) at the loss of MLH1 and PMS2, 66.7% (36/54) at the loss of MSH2 and MSH6, and 47.9% (11/23) at the isolated loss of PMS2, respectively. There is no correlation between minimal shift group or major shift group and clinicopathological features.ConclusionMMR-deficient ECs exhibit a high frequency of minimal microsatellite shifts, particularly in cases with isolated loss of MSH6. The combination of MMR-IHC and MSI-PCR assays could enhance the accuracy of MSI detection, thereby facilitating more precise treatment strategies of ECs.

The role of dysbiosis in shaping host immunity in endometrial cancer development

In recent years, research into the background of carcinogenic processes has increasingly focused on the role of the tumor microenvironment (TME) in tumorigenesis. In addition to the presence of tumor cells and non-malignant components, which include immune cells, extracellular matrix elements, stroma, and endothelial cells, the microbiome is now increasingly being classified as an integral part of the TME. The establishment of the Human Microbiome Project (HMP) in 2007 along with the development of next-generation sequencing (NGS) techniques proved to be a breakthrough in terms of human microbiota research, shedding new light on the existing knowledge of microorganisms inhabiting various niches of the human body and their functions. Emerging scientific evidence from preclinical and clinical studies indicates significant differences in the microbiome composition between tumor tissues and benign controls. The presence of specific pathogenic strains within a tissue may play a key role in the initiation and progression of inflammation, which not only may be directly responsible for the stimulation of tumorigenic processes but may also affect the destabilization of the host genome, causing significant disruption of its metabolism. The role of microorganisms in the induction and promotion of pathological processes, including cancer, has been confirmed in many studies to date. Recent years of research on the microbiota of the female reproductive tract (FRT) have not only indicated that the endometrium has its unique microbial composition but have also made it possible to point out differences in composition between the microbiome of healthy and tumor-lesioned tissue, suggesting a potential role for dysbiotic disorders in the pathogenesis of endometrial cancer (EC). In this review, we aim to highlight the complex interplay between bacterial interactions and host immunity, and how this phenomenon contributes to the development and progression of endometrial cancer.

Biomarkers and immunotherapy in endometrial cancer: mechanisms and clinical applications

Advanced endometrial cancer (EC) poses significant therapeutic challenges due to molecular heterogeneity and immune evasion. Immune checkpoint inhibitors (ICIs) show promise, particularly in mismatch repair-deficient (MMRd) and POLE-mutated subtypes, but resistance remains a barrier. This review synthesizes recent advances in biomarker-driven immunotherapy for EC, focusing on predictive biomarkers (e.g., LRP2, FANCE, MSH2, miRNA signatures), combination strategies (ICIs with anti-angiogenics or PARP inhibitors), and challenges in clinical translation. We highlight the impact of tumor microenvironment components, emerging technologies like machine learning, and future directions for personalized immunotherapy. Standardizing biomarker testing and optimizing trial designs will be critical to overcome resistance and improve outcomes.

Combination of anlotinib with immunotherapy enhanced both anti-angiogenesis and immune response in high-grade serous ovarian cancer

BackgroundHigh-grade serous ovarian cancer (HGSOC) poses significant treatment challenges due to frequent recurrence and resistance to conventional therapies. Combination of anlotinib with immunotherapy have showed promise in various cancers, but its impact on HGSOC remains to be fully elucidated.MethodsA retrospective analysis was performed on 36 HGSOC patients treated with anlotinib-based therapies, including both monotherapy and combination treatment with anti-PD-L1/anti-PD-1 antibody (aPD-L1/aPD-1). Peripheral blood mononuclear cell-derived patient-derived xenograft (PBMC-PDX) model was established from drug-resistant recurrent HGSOC patient-derived tumor cells, and single-cell RNA sequencing (scRNA-seq) was conducted to dissect the TME following treatment with anlotinib, anlotinib + aPD-L1 and anlotinib + aPD-1.ResultsClinical analysis revealed a disease control rate (DCR) of 71.43% for anlotinib monotherapy, which improved to 100% when combined with aPD-L1/aPD-1. In PBMC-PDX models, treatment evaluation showed that anlotinib decreased tumor volume, an effect further enhanced by its combination with aPD-L1. scRNA-seq analysis demonstrated that anlotinib reduced the proportions of myofibroblastic cancer-associated fibroblasts and ESM1+ endothelial cells, resulting in decreased angiogenesis. The combination of anlotinib and aPD-L1 further amplified these effects, promoting CD8+ T cell infiltration and reversing T cell exhaustion, whereas anlotinib + aPD-1 showed limited efficacy in this regard. Additionally, anlotinib + immunotherapy induced a shift toward M1 polarization of myeloid cells, enhanced anti-tumor activity, and inhibited immune escape. Cell-cell communication analysis revealed reduced APP-CD74 signaling and increased CD99-CD99 signaling, which might contribute to immune activation.ConclusionThe combination of anlotinib and aPD-L1 effectively modulates the HGSOC tumor microenvironment by inhibiting angiogenesis, enhancing immune infiltration, and reversing T cell exhaustion.

Immunotherapy for high-grade endometrial stromal sarcoma: a narrative review bridging molecular insights to clinical translation

High-grade endometrial stromal sarcoma (HGESS) is a rare solid malignancy characterized by a poor prognosis and highly aggressive behavior. Currently, surgical resection remains the primary treatment for HGESS. Radiotherapy and chemotherapy can address local symptoms and enhance the quality of life of patients; however, they do not improve patient survival rates. Recent studies have found that the molecular characteristics of HGESS (such as gene fusions like YWHAE-NUTM2, ZC3H7B-BCOR, etc.) drive the high invasiveness of the tumor. Although immunotherapy has achieved significant breakthroughs in solid tumors, the immunosuppressive microenvironment of HGESS remains a key focus for future immunotherapy research. This narrative review comprehensively analyzes the interactions between alterations in the tumor microenvironment and immune escape mechanisms in HGESS. It also proposes a diverse range of immunotherapy options, including Oncolytic virus therapy, adoptive cell transfer therapy, immune checkpoint inhibitors, cancer vaccines, and combination strategies. We hold the view that a profound comprehension of the molecular immunological characteristics of HGESS, the identification of effective biomarkers, and the implementation of well-designed clinical studies are the indispensable routes to successfully translate immunotherapy into an effective treatment for this intractable HGESS.

SLC2A1 and MPST as diagnostic and prognostic biomarkers of potential endometrial cancer

Uterine corpus endometrial carcinoma (UCEC) is the predominant neoplasm affecting the female reproductive system. Early diagnosis of UCEC is crucial for improving patient survival rates. In this study, we selected and investigated two specific genes associated with hydrogen sulfide(H2S): SLC2A1, which encodes a glucose transporter, and MPST, which encodes 3-mercaptopyruvate thiotransferase. Both SLC2A1 and MPST have been identified as important regulators in cancer. The objective of this study was to investigate the potential significance of SLC2A1 and MPST in terms of UCEC diagnosis and prognosis. Our analysis using Kaplan-Meier survival curves and receiver operating characteristic (ROC) curves demonstrated robust diagnostic and prognostic significance for both SLC2A1 and MPST. Moreover, our research revealed a significant association between the expression levels of SLC2A1 and MPST, immune cell infiltration, immune checkpoint gene presence, and TP53 in UCEC tissues. Furthermore, we observed that DNA methylation status of the CpG island of SLC2A1 and the MPST gene is associated with UCEC prognosis. These findings suggest that SLC2A1 and MPST genes hold promise in distinguishing endometrial cancer patients from normal cases, highlighting their diagnostic and prognostic potential as biomarkers for UCEC. These results offer encouraging prospects for targeted therapies.

Prognostic significance and immune infiltration analysis of HMGA2 in endometrial cancer

BackgroundHMGA2, as a transcription factor, facilitates oncogenesis and malignant progression by coordinating cell cycle dysregulation, compromising DNA repair machinery, and suppressing cancer cell apoptosis. However, its roles in prognostication and tumor immune microenvironment modulation in endometrial cancer (EC) remain incompletely defined.MethodsWe systematically analyzed HMGA2 expression patterns and clinical prognostic value in EC using bioinformatics strategies, including TCGA and GTEX data mining, as well as single gene expression analysis. Functional enrichment analysis (GSEA and KEGG) identified HMGA2-associated pathways. The correlation between HMGA2 and immune infiltration was assessed via TIMER and TISIDB. Subsequent in vitro (proliferation, migration, colony formation) and in vivo (xenograft models) experimental were used to validate HMGA2’s role in promoting EC progression. The correlation between HMGA2 and macrophage markers (CD86 and CD206) was validated through clinical tissue samples by IHC. Finally, a recurrence-predictive nomogram incorporating HMGA2 with clinicopathological parameters was established.ResultsHMGA2 exhibited significant upregulation in endometrial cancer (EC) tissues and correlated with poor patient prognosis. Immunoassay showed that high expression of HMGA2 was negatively correlated with infiltration of various immune cells, especially M1 macrophages. Cytological experiments showed that knocking down HMGA2 significantly inhibited EC cell proliferation, migration, invasion, and drug resistance, while overexpression of HMGA2 promoted the above phenotype; Animal experiments showed that knocking down HMGA2 significantly inhibited the growth of EC tumors and the expression of M1 macrophage marker CD86. The combination of HMGA2 inhibitors and targeted macrophage immunotherapy (CD47 monoclonal antibody) had the better tumor suppression effect. Clinical sample analysis found that high expression of HMGA2 was significantly negatively correlated with CD86 and positively correlated with CD206 expression. Patients with low HMGA2 expression showed enhanced immune therapy responsiveness. The nomogram model based on HMGA2 and clinical pathological parameters showed better predictive performance (AUC=0.855, sensitivity=79.0%, specificity=76.8%).ConclusionHMGA2 is a potential diagnostic and prognostic biomarker for the EC. HMGA2 may drive the occurrence and development of EC by inhibiting the infiltration of immune cells, especially M1 macrophages. Therapeutic targeting of HMGA2 is a novel strategy for EC intervention.

Lymphoepithelioma-like carcinoma with carcinosarcoma of the endometrium: a case report and literature review

This report describes a 56-year-old female diagnosed with lymphoepithelioma-like carcinoma with carcinosarcoma of the endometrium (LELCCSE). She experienced vaginal bleeding and lower abdominal discomfort without any obvious cause following six years of menopause. She sought treatment at our hospital in Hangzhou, China. An ultrasound examination revealed a hypoechoic mass within the uterus. Subsequently, a biopsy confirmed it as lymphoepithelioma-like carcinoma (LELC) with carcinosarcoma.The patient underwent a total hysterectomy, bilateral salpingo-oophorectomy, and associated lymphadenectomy. The postoperative pathology suggested LELC complicated with carcinosarcoma and an IIC grade by the 2023 FIGO staging system. She received adjuvant chemotherapy and radiotherapy without any molecular testing due to her financial constraints. A gene which encodes the catalytic subunit of DNA polymerase epsilon(POLE) mutation was found by the retrospective molecular testing; however, no recurrence or metastasis occurred after 12 follow-up months.

The immune microenvironment in endometrial carcinoma: mechanisms and therapeutic targeting

Endometrial carcinoma (EC) represents one of the most prevalent malignancies within the female reproductive system. The frequency of its occurrence is on the rise annually, and patients diagnosed at advanced stages face a less favorable prognosis. Recent studies have highlighted the significant influence of the tumor immune microenvironment (TME) on the initiation, progression, metastasis, and therapeutic resistance of endometrial cancer. The TME encompasses various components such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), immune cells, and the extracellular matrix (ECM). These elements contribute to an immunosuppressive milieu by secreting cytokines, extracellular vesicles (EVs), and engaging immune checkpoint pathways like PD-1/PD-L1, thereby supporting tumor immune evasion and resistance to treatment. This review synthesizes current understanding of the EC-TME, focusing on the distinct roles and interactions of its key constituents within the context of EC biology. Furthermore, we explore the rationale and progress for novel therapeutic strategies targeting the TME, such as immune checkpoint inhibitors, combination therapies, and nano delivery systems leveraging EVs, aiming to provide insights for improving EC patient outcomes.

Epidemiology, molecular typing, microbiome-immune interactions and treatment strategies of endometrial cancer: a review

This review focuses on the field of endometrial cancer. Since 2020, there have been 417,367 new cases of endometrial cancer diagnosed globally and 97,370 deaths reported. Endometrial cancer ranks second in terms of incidence among female genital malignancies and third in terms of mortality among gynecological cancers. The stage, grade, and histological subtype of endometrial cancer were closely correlated with the risk of recurrence and prognosis for survival. Meanwhile, endometrial cancer exhibits significant biological heterogeneity. The complex interactions among the reproductive tract, host cells, and the microbial environment may harbor novel disease mechanisms. In this review, we provide an overview of the epidemiological characteristics, major risk factors, histological and molecular subtypes of endometrial cancer, as well as explore the associations between the female reproductive tract microbiome, immunity, and cancer progression. We also identify the specific roles of different cytokines in the pathophysiology of endometrial cancer. By integrating findings from diverse research fields, this comprehensive review offers an in-depth understanding of the multidimensional nature of endometrial cancer and highlights the significant potential and promising avenues that microbiological factors present for advancing future cancer research and guiding the development of innovative therapeutic strategies.

Case report: Reproductive organ preservation and subsequent pregnancy for an infertility patient with lynch syndrome-associated synchronous endometrial cancer and colon cancer after treatment with a PD-1 checkpoint inhibitor

Currently, immune checkpoint inhibitors (ICIs) are the mainstay of treatment for Lynch syndrome patients. However, the tumor regression features in radiology and pathology are inconsistent for patients who are treated with ICIs, which sometimes confuses surgical decision-making. Here, we report a case in which a 36-year-old patient suffering from infertility was diagnosed with Lynch syndrome-associated synchronous endometrial cancer and colon cancer, and persistently enlarged left iliac paravascular lymph nodes were detected after receiving sintilimab treatment, a programmed cell death 1 (PD-1) receptor inhibitor. Fortunately, when she was about to undergo hysterectomy and bilateral salpingo-oophorectomy, intraoperative pathology examination did not reveal any cancer cells in these lymph nodes, and therefore, her reproductive organs were preserved. Later, the patient successfully conceived and gave birth to a healthy male neonate with no immune-related adverse events (irAEs) during an 11-month follow-up. This case indicates that surgeons should carefully inspect the imaging characteristics after immunotherapy and that organ preservation is possible even for patients who fail to achieve complete clinical regression, which is especially important for female patients of childbearing age.

Case Report: Cord blood-derived natural killer cells as new potential immunotherapy drug for solid tumor: a case study for endometrial cancer

Adoptive transfer of natural killer (NK) cells represents a viable treatment method for patients with advanced malignancies. Our team previously developed a simple, safe, and cost-effective method for obtaining high yields of pure and functional NK cells from cord blood (CB) without the need for cell sorting, feeder cells, or multiple cytokines. We present the case of a 52-year-old female patient diagnosed with poorly differentiated stage IVB (T3N2M1) endometrial cancer, who exhibited leukemoid reaction and pretreatment thrombocytosis as paraneoplastic syndromes. The patient received two courses of CB-derived NK (CB-NK) cell immunotherapy between March and September 2022, due to her extremely low NK cell activity. Two available CB units matched at 8/10 HLA with KIR-mismatch were chosen, and we were able to produce NK cells with high yield (>1.0×1010 NK cells), purity (>90%), and function (>80%) from CB without cell sorting, feeder cells, or multiple cytokines. These cells were then adoptively transferred to the patient. No adverse effects or graft-versus-host disease were observed after infusion of CB-NK cells. Our clinical experience supports the efficacy of CB-NK cell treatment in increasing NK cell activity, depleting tumor activity, improving quality of life, and reducing the size of abdominal and pelvic masses with the disappearance of multiple lymph node metastases through the regulation of systemic antitumor immunity. Remarkably, the white blood cell and platelet counts decreased to normal levels after CB-NK cell immunotherapy. This clinical work suggests that CB-NK cell immunotherapy holds promise as a therapeutic approach for endometrial cancer.

Construction of a prognostic model for endometrial cancer related to programmed cell death using WGCNA and machine learning algorithms

BackgroundProgrammed cell death (PCD) refers to a regulated and active process of cellular demise, initiated by specific biological signals. PCD plays a crucial role in the development, progression, and drug resistance of uterine corpus endometrial carcinoma (UCEC), making the exploration of its relationship with UCEC prognosis highly clinically relevant.MethodsData from UCEC patients and control cohorts were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were identified and subsequently intersected with a PCD gene set to discern PCD-related differentially expressed genes (PCD-DEGs). To isolate core prognostic PCD-DEGs, methods including consistency clustering analysis, weighted gene co-expression network analysis (WGCNA), univariate Cox regression analysis, and five machine learning techniques for dimensionality reduction were utilized. Validation of three core prognostic PCD-DEGs was conducted using RT-qPCR, and these genes were used to develop a prognostic model. Additionally, an analysis of drug sensitivity was performed.ResultsConsistency clustering analysis revealed significant differences in prognosis and tumor microenvironment among subtypes, strongly associated with various immune subtypes. The three core prognostic PCD-DEGs identified—SRPX, NT5E, and ATP6V1C2—were instrumental in constructing the lasso prognostic model and nomogram. Receiver Operating Characteristic (ROC) curve analysis confirmed the model’s strong prognostic performance and clinical applicability. The high-risk group exhibited lower tumor mutation frequencies, a higher propensity for immune escape, reduced response to immune therapy, and potential benefits from potent chemotherapy drugs.ConclusionThis study developed a prognostic model related to PCD for UCEC using comprehensive bioinformatics analyses. The model demonstrates robust predictive performance and holds significant potential for clinical application, thereby facilitating precise stratification and personalized treatment of UCEC patients.

CD8+ T cell activation in endometrial cancer: prognostic implications and potential for personalized therapy

BackgroundAs an important component in preventing the progression of endometrial cancer, CD8 T cells play a crucial role in this process and are important targets for immunotherapy. However, the status of CD8+ T cells in endometrial cancer and the key genes influencing their activation still remain to be elucidated.MethodsGenes associated with the activation of CD8+ T cells were identified through differential analysis and weighted gene co-expression network analysis (WGCNA). A risk score model was constructed using the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression. The clinical characteristics and differences between the high-risk group and the low-risk group were explored, and the applicability of the model to chemotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors, and immune checkpoint inhibitors was evaluated. The characteristics of the model at the single-cell level were studied, and the tumor-suppressive effect of ASB2 was verified through experiments on endometrial cancer cells.ResultsA risk model based on genes related to the activation of CD8+ T cells was constructed, and the prognostic differences were verified using the Kaplan-Meier curve. A nomogram was designed to predict the survival probability. Pathway analysis showed that it was related to metabolism and DNA repair. There were significant differences between the high-risk and low-risk groups in terms of tumor mutational burden (TMB), checkpoint molecules, and major histocompatibility complex (MHC) class I molecules, and they had different sensitivities to different therapies. The tumor-suppressive effect of ASB2 was confirmed in experiments on cell proliferation, invasion, and migration.ConclusionThis study provides a predictive tool for endometrial cancer. The classification based on the status of CD8+ T cells can distinguish the prognosis and treatment response, highlighting the potential of this model in personalized treatment.

Global research trends and focus on immunotherapy for endometrial cancer: a comprehensive bibliometric insight and visualization analysis (2012-2024)

BackgroundThis study conducted a novel systematic bibliometric and visualization analysis of global literature on immunotherapy for endometrial cancer (EC) to explore dynamic trends, research hotspots, and emerging topics, providing valuable references for future research.MethodsArticles and reviews on EC immunotherapy published between 2012 and August 2024 were retrieved from the Web of Science Core Collection (WoSCC). Bibliometric tools, CiteSpace and VOSviewer, were used to analyze clustering patterns and research dynamics.ResultsA total of 861 articles were contributed by 5,331 authors from 1,392 institutions across 58 countries or regions, involving 1,823 keywords. China demonstrated outstanding performance in this field, contributing over 40% of the total publications and ranking first in publication volume. However, the total citation counts for publications from China lags that of the United States, highlighting the latter’s leading position and areas for further improvement in China’s research efforts. The University of Texas Medical Anderson Cancer Center and Nanjing Medical University were the two institutions with the highest number of publications. In terms of authorship, research teams led by Bosse, Tjalling, and Creutzberg, Carien L made significant contributions to advancing the field. Among individual publications, the work by Talhouk et al. achieved the highest average annual citation count of 70.88, demonstrating its profound impact. In terms of journals, Gynecologic Oncology emerged as a pivotal academic platform, publishing numerous articles and achieving the highest co-citation frequency. Additionally, Frontiers in Oncology, Frontiers in Immunology, and Frontiers in Genetics have become some of the most active and rapidly developing journals in recent years. Research hotspots are concentrated on themes such as the “Tumor Immune Microenvironment”, “Immune Checkpoint Inhibitors”, and “Targeted Therapy”. Recent trends and frontier research focus on the combined application of immune checkpoint inhibitors with other therapies, research on the application of nanotechnology in immunotherapy, and the integration of artificial intelligence to enhance precision medicine. Additionally, efforts are increasingly directed toward advancing various immunotherapy strategies from basic research to clinical applications.ConclusionsThis comprehensive analysis reveals rapid advancements and significant potential in EC immunotherapy. Strengthening international collaboration and addressing barriers in the translation of research to clinical practice will drive further progress in this promising field.

OnmiMHC: a machine learning solution for UCEC tumor vaccine development through enhanced peptide-MHC binding prediction

The key roles of Major Histocompatibility Complex (MHC) Class I and II molecules in the immune system are well established. This study aims to develop a novel machine learning framework for predicting antigen peptide presentation by MHC Class I and II molecules. By integrating large-scale mass spectrometry data and other relevant data types, we present a prediction model OnmiMHC based on deep learning. We rigorously assessed its performance using an independent test set, OnmiMHC achieves a PR-AUC score of 0.854 and a TOP20%-PPV of 0.934 in the MHC-I task, which outperforms existing methods. Likewise, in the domain of MHC-II prediction, our model OnmiMHC exhibits a PR-AUC score of 0.606 and a TOP20%-PPV of 0.690, outperforming other baseline methods. These results demonstrate the superiority of our model OnmiMHC in accurately predicting peptide-MHC binding affinities across both MHC-I and MHC-II molecules. With its superior accuracy and predictive capability, our model not only excels in general predictive tasks but also achieves significant results in the prediction of neoantigens for specific cancer types. Particularly for Uterine Corpus Endometrial Carcinoma (UCEC), our model has successfully predicted neoantigens with a high binding probability to common human alleles. This discovery is of great significance for the development of personalized tumor vaccines targeting UCEC.

Establishment of a prognostic signature and immune infiltration characteristics for uterine corpus endometrial carcinoma based on a disulfidptosis/ferroptosis-associated signature

BackgroundDisulfidptosis and ferroptosis are two different programmed cell death pathways, and their potential therapeutic targets have important clinical prospects. Although there is an association between the two, the role of genes associated with these two forms of cell death in the development of endometrial cancer remains unclear.MethodsIn this study, RNA sequencing (RNA-seq) and clinical data were obtained from public databases, and comprehensive analysis methods, including difference analysis, univariate Cox regression, and Least Absolute Shrinkage and Selection Operator (LASSO) analysis were used to construct a disulfidptosis/ferroptosis-related genes (DFRGs) prognostic signature. To further explore this new feature, pathway and functional analyses were performed, and the differences in gene mutation frequency and the level of immune cell infiltration between the high- and low-risk groups were studied. Finally, we validated the prognostic gene expression profile in clinical samples.ResultsWe identified five optimal DFRGs that were differentially expressed and associated with the prognosis of uterine corpus endometrial carcinoma (UCEC). These genes include CDKN2A, FZD7, LCN2, ACTN4, and MYH10. Based on these DFRGs, we constructed a robust prognostic model with significantly lower overall survival in the high-risk group than in the low-risk group, with differences in tumor burden and immune invasion between the different risk groups. The expression of two key genes, ACTN4 and LCN2, was verified by immunohistochemistry and RT-qPCR.ConclusionThis study established a clinical prognostic model associated with disulfidptosis/ferroptosis-related genes, and the expression characteristics of key genes were validated in clinical samples. The comprehensive assessment of disulfidptosis and ferroptosis provides new insights to further guide patient clinical management and personalized treatment.

Efficacy and safety of PD-1/PD-L1 inhibitors in advanced or recurrent endometrial cancer: a meta-analysis with trial sequential analysis of randomized controlled trials

BackgroundThe combination of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors with chemotherapy (CT) is currently under evaluation as a first-line treatment for advanced or recurrent endometrial cancer (EC). This study sought to assess the efficacy and safety of this therapeutic combination in patients with advanced or recurrent EC.MethodsWe performed an exhaustive review of randomized controlled trials (RCTs) up to September 25, 2024, examining the efficacy and safety of combining PD-1/PD-L1 inhibitors with CT versus CT alone (or plus placebo) in advanced or recurrent EC. Efficacy was measured by progression-free survival (PFS) and overall survival (OS), while safety was assessed by the incidence of any grade or grade ≥ 3 adverse events (AEs). We calculated hazard ratios (HRs) for PFS and OS, as well as risk ratios (RRs) for AEs, each accompanied by 95% confidence intervals (CIs). To evaluate heterogeneity, we employed Cochran’s Q test, I2 statistics, and 95% prediction intervals (PIs). Trial sequential analysis (TSA) was conducted using R Version 4.3.1, STATA Version 12.0, and TSA Version 0.9.5.10 Beta software.ResultsOur analysis incorporated 6 studies, encompassing a total of 2,954 patients. The combination of PD-1/PD-L1 inhibitors with CT significantly improved PFS (HR = 0.617, 95% CI: 0.506-0.752; 95% PI: 0.334-1.140) and OS (HR = 0.774, 95% CI: 0.664-0.902; 95% PI: 0.553-1.083) compared to CT alone (or plus placebo) in the overall population. Subgroup analysis based on mismatch repair (MMR) status revealed pronounced benefits in PFS and OS for patients with deficient MMR (dMMR) (PFS: HR = 0.344, 95% CI: 0.269-0.438; 95% PI: 0.231-0.510; OS: HR = 0.371, 95% CI: 0.245-0.562; 95% PI: 0.025-5.461) compared to those with proficient MMR (pMMR) (PFS: HR = 0.772, 95% CI: 0.627-0.950; 95% PI: 0.394-1.512; OS: HR = 0.996, 95% CI: 0.692-1.435; 95% PI: 0.021-47.662). Although there was no observed difference in the incidence of any grades AEs (RR = 0.994, 95% CI: 0.982-1.006; 95% PI: 0.978-1.009), the risk of grade ≥ 3 AEs was elevated in the group receiving PD-1/PD-L1 inhibitors in combination with CT (RR = 1.132, 95% CI: 1.023-1.252; 95% PI: 0.836-1.532).ConclusionThe combination of PD-1/PD-L1 inhibitors with CT significantly improved PFS and OS in advanced or recurrent EC patients, with particularly pronounced benefits observed in those with dMMR. Clinicians can tailor treatment strategies according to individual patient characteristics to optimize therapeutic outcomes, while remaining alert to the possibility of AEs in clinical practice.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024595455.

Unveiling immunogenic characteristics and neoantigens in endometrial cancer with POLE hotspot mutations for improved immunotherapy

BackgroundImmunotherapy, especially with the use of immune checkpoint inhibitors, has demonstrated efficacy for a variety of malignant tumors. However, the potential of immunotherapy for endometrial cancer (EC) with POLE mutations remains underexplored.MethodsWe utilized multiple databases and clinical specimens to investigate the immunogenicity profiles of EC patients carrying POLE mutations. One particular hotspot mutation POLEP286R was identified and further studied. Consequently, by constructing human leukocyte antigen (HLA) tetramers and incubating them with patients’ peripheral blood mononuclear cells (PBMCs), T cells capable of recognizing the POLEP286R mutation were sorted for further transcriptomic, proteomic and T-cell receptor (TCR) sequencing analyses and for an organoid EC model.ResultsTumor- and immune-related pathways were shown to be activated in the POLEP286R mutant group. Importantly, by using an organoid model of EC, we further confirmed the antitumor potential of T cells that were specific to the POLEP286R mutation.ConclusionsOur study uncovers the pronounced immunogenicity of POLE-mutant EC and characterizes neoantigens that are unique to the POLEP286R mutation, thus providing a promising new immunotherapeutic strategy for EC.

Efficacy and safety of lenvatinib plus pembrolizumab in patients with advanced and recurrent endometrial cancer: a systematic review and meta-analysis

BackgroundVarious trials have demonstrated the clinical benefits of lenvatinib plus pembrolizumab in patients with advanced or recurrent endometrial cancer, regardless of mismatch repair (MMR) status or histologic subtype. The majority of the previously published trials had small sample sizes. Here, we aimed to assess the reported efficacy and safety profile of lenvatinib plus pembrolizumab in patients with advanced and recurrent endometrial cancer.MethodsWe utilized the Cochrane Library, PubMed, Web of Science and Embase databases to identify clinical trials evaluating the efficacy and safety of lenvatinib plus pembrolizumab in patients with advanced and recurrent endometrial cancer. The outcomes analyzed were progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the disease control rate (DCR) and the incidence of adverse events (AEs). Subgroup analysis was conducted on the basis of MMR status (deficient, dMMR or proficient, pMMR).ResultsFour trials (582 patients) were included. The pooled ORR was 32.7% [95% confidence interval (CI): 28.9–36.5]. Subgroup analysis revealed an ORR of 48.1% (95% CI: 26.1–70.2) for dMMR group and 33.1% (95% CI: 25.7–40.6) for pMMR group. The pooled DCR was 74.9% (95% CI: 71.3–78.4%). Subgroup analysis revealed a DCR of 81.0% (95% CI: 64.5–97.6) for the dMMR group and 76.3% (95% CI: 66.3–86.3) for the pMMR group. Follow-up was reported in all included studies. The median range time of PFS and OS was 5.3 months-258 days and 17.2 months-not reached, respectively. Regarding safety, the overall pooled proportions of any-grade AE and AEs ≥ grade 3 were 95.8% (95% CI: 89.5–100.0) and 80.2% (95% CI: 59.9–100.0), respectively.ConclusionLenvatinib plus pembrolizumab showed a relevant clinical benefit and significant toxicity in patients with advanced and recurrent endometrial cancer. Further studies encompassing long-term outcomes are warranted.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=522160/, identifier CRD42024522160.

Tumor immune microenvironment in endometrial cancer of different molecular subtypes: evidence from a retrospective observational study

ObjectiveTumor immune microenvironmental features may predict survival and guide treatment. This study aimed to comprehensively decipher the immunological features of different molecular subtypes of endometrial cancer.MethodsIn this retrospective study, 26 patients with primary endometrial cancer and four with recurrent disease treated in our center from December 2018 to November 2021 were included. Next-generation sequencing was performed on tumor samples. Patients were classified into four subtypes, including POLE mutant, microsatellite instability high (MSI-H), no specific molecular profile (NSMP) and TP53 mutant subtypes. Tumor-infiltrating immune cells were quantified using multiplex immunofluorescence assays.ResultsOf the 26 primary endometrial cancer cases, three were POLE mutant, six were MSI-H, eight were NSMP and nine were TP53 mutant. Of the four recurrent cases, two belonged to the NSMP subtype and two belonged to the TP53 mutant subtype. The tumor mutation burden (TMB) levels of POLE mutant and MSI-H cases were significantly higher than that of the other two subtypes (p< 0.001). We combined POLE mutant and MSI-H subtypes into the TMB high (TMB-H) subtype. The TMB-H subtype showed a high degree of infiltration of CD8+ T cells. In the NSMP subtype, the overall degree of intra-tumoral infiltrating immune cells was low. In the TP53 mutant subtype, the densities of both PD-L1+ macrophages (p = 0.047) and PD-1+ T cells (p = 0.034) in tumor parenchyma were the highest among the four subtypes.ConclusionEndometrial cancer of TMB-H, NSMP and TP53 mutant subtypes displayed phenotypes of normal immune response, absence of immune infiltration, and suppressed immune response, respectively. These features may provide mechanistic explanations for the differences in patients’ prognosis and efficacy of immune checkpoint blockade therapies among different endometrial cancer subtypes.

Cost-effectiveness analysis of dostarlimab plus carboplatin-paclitaxel as first-line treatment for advanced endometrial cancer

BackgroundA recent phase III clinical trial (NCT03981796) evaluated the efficacy and safety of dostarlimab combined with carboplatin-paclitaxel (DOS-CP) compared to placebo combined with carboplatin-paclitaxel (PLB-CP) as a first-line treatment for advanced endometrial cancer (EC). The NCT03981796 trial demonstrated that DOS-CP significantly improved progression-free survival and overall survival of patients with advanced EC while maintaining an acceptable safety profile. However, DOS-CP is expensive and its cost-effectiveness has not been evaluated. This study aims to evaluate the cost-effectiveness of DOS-CP compared to PLB-CP as a first-line treatment for advanced EC from the perspective of the Chinese healthcare system.MethodsA Markov model with three health states was developed to evaluate the cost-effectiveness of DOS-CP as a first-line treatment for advanced EC. Clinical efficacy data were derived from the NCT03981796 trial, and drug costs were determined based on national tender prices. Other costs and utility values were obtained from published literature. The outcomes assessed included total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The robustness of the model was assessed through one-way sensitivity analysis and probabilistic sensitivity analysis.ResultsIn comparison to PLB-CP, the ICER of DOS-CP was $98,276.61/QALY for the overall population, $53,063.61/QALY for the dMMR subgroup, and $124,088.56/QALY for the pMMR subgroup. All of these ICER values were higher than the willingness-to-pay threshold of $38,201 per QALY. The most important variable that affected the results of the model was the discount rate, the cost of dostarlimab, and the utility value for progressive disease.ConclusionFrom the perspective of the Chinese healthcare system, DOS-CP is unlikely to be a cost-effective first-line treatment option for advanced EC.

Integrated analysis and experiments uncover the function of disulfidptosis in predicting immunotherapy effectiveness and delineating immune landscapes in uterine corpus endometrial carcinoma

IntroductionRecently, a novel type of metabolic-regulated cell demise titled disulfidptosis has been discovered. Studies have demonstrated its importance in immune responses against cancer and its impact on the proliferation of cancer cells. Nonetheless, the precise mechanism and roles of disulfidptosis are not fully understood, particularly regarding the prognosis for individuals with uterine corpus endometrial carcinoma (UCEC).MethodsIn this research, a distinctive disulfidptosis pattern was developed in UCEC, and by utilizing Non-negative Matrix Factorization (NMF) on 23 disulfidptosis related genes within the TCGA database, 3 distinct subgroups were distinguished. To collect data, we acquired gene expression profiles, somatic mutation information, copy number variation data, and corresponding clinical data from the TCGA and GEO database, specifically from UCEC patients. Cell line experiments and immunohistochemical (IHC) staining were conducted to validate the role of the LRPPRC in proliferation, migration and invasion.ResultsThe genetic features and immune microenvironment of these subgroups were examined. It is worth mentioning that these subgroups offer important insights into comprehending the tumor microenvironment (TME) and the response of patients to immunotherapy and chemotherapy. Moreover, a disulfidptosis model was developed and validated, demonstrating a high level of accuracy in predicting the prognosis and outcomes of immunotherapy in UCEC patients. Additionally, a novel biomarker, LRPPRC, was identified, which can server as a promising predictor for forecasting prognosis in UCEC patients, with validation through tissue microarray staining and cell line experiments.DiscussionThis study has designed a classification system and a disulfidptosis model for UCEC, in addition to identifying a new biomarker, LRPPRC, for UCEC. These advancements serve as reliable and positive indicators for predicting outcomes and the efficacy of immunotherapy for each UCEC patient.

The immunological and prognostic significance of the diabetes mellitus-related gene WFS1 in endometrial cancer

BackgroundDiabetes is associated with the incidence and prognosis of various malignancies, most notably endometrial cancer (EC). This study investigated the connection between diabetes and EC, with a specific focus on elucidating the biological implications of the diabetes mellitus (DM)-related gene WFS1.MethodsUsing the CTD, GeneCards, and GSEA databases, we identified WFS1 as a diabetes-related gene and then conducted an extensive investigation focusing on WFS1 in the context of EC. First, we identified WFS1 as the target gene and obtained EC data from the TCGA database. Then, comprehensive analyses and verification experiments, including differential expression analysis, prognostic modeling, functional enrichment analysis, gene mutation profiling, assessment of immune cell infiltration, immunophenoscore (IPS), tumor stemness index scoring, drug sensitivity analysis, single-cell transcriptomic analysis, glycolytic pathway analysis, and clinical verification, were performed to comprehensively evaluate the clinical value of WFS1 in EC.ResultsThe EC group had significantly lower WFS1 expression, with an AUC of 0.857 for the ROC diagnostic curve. Overall survival analysis revealed that WFS1 was an independent risk factor for EC; low WFS1 expression was correlated with a poor prognosis. Stemness index analysis revealed that decreased WFS1 expression was associated with increased tumor grade and enhanced tumor stemness, suggesting increased malignancy of EC. In addition, WFS1 expression was correlated with tumor microenvironment features such as immune cell infiltration. WFS1 was also associated with tumor drug resistance.ConclusionEC patients with low WFS1 expression have a worse prognosis. WFS1 can be used as diagnostic and prognostic marker for EC.

Single-cell RNA sequencing in endometrial cancer: exploring the epithelial cells and the microenvironment landscape

Single-cell RNA sequencing (scRNA-seq) technology has emerged as a powerful tool for dissecting cellular heterogeneity and understanding the intricate biology of diseases, including cancer. Endometrial cancer (EC) stands out as the most prevalent gynecological malignancy in Europe and the second most diagnosed worldwide, yet its cellular complexity remains poorly understood. In this review, we explore the contributions of scRNA-seq studies to shed light on the tumor cells and cellular landscape of EC. We discuss the diverse tumoral and microenvironmental populations identified through scRNA-seq, highlighting the implications for understanding disease progression. Furthermore, we address potential limitations inherent in scRNA-seq studies, such as technical biases and sample size constraints, emphasizing the need for larger-scale research encompassing a broader spectrum of EC histological subtypes. Notably, a significant proportion of scRNA-seq analyses have focused on primary endometrioid carcinoma tumors, underscoring the need to incorporate additional histological and aggressive types to comprehensively capture the heterogeneity of EC. By critically evaluating the current state of scRNA-seq research in EC, this review underscores the importance of advancing towards more comprehensive studies to accelerate our understanding of this complex disease.

High DNA methylation age deceleration defines an aggressive phenotype with immunoexclusion environments in endometrial carcinoma

Like telomere shortening, global DNA hypomethylation occurs progressively with cellular divisions or in vivo aging and functions as a mitotic clock to restrain malignant transformation/progression. Several DNA-methylation (DNAm) age clocks have been established to precisely predict chronological age using normal tissues, but show DNAm age drift in tumors, which suggests disruption of this mitotic clock during carcinogenesis. Little is known about DNAm age alterations and biological/clinical implications in endometrial cancer (EC). Here we address these issues by analyzing TCGA and GSE67116 cohorts of ECs. Horvath clock analysis of these tumors unexpectedly revealed that almost 90% of them exhibited DNAm age deceleration (DNAmad) compared to patient chronological age. Combined with an additional clock named Phenoage, we identified a subset of tumors (82/429) with high DNAmad (hDNAmad+) as assessed by both clocks. Clinically, hDNAmad+ tumors were associated with advanced diseases and shorter patient survival, compared to hDNAmad- ones. Genetically, hDNAmad+ tumors were characterized by higher copy number alterations (CNAs) whereas lower tumor mutation burden. Functionally, hDNAmad+ tumors were enriched with cell cycle and DNA mismatch repair pathways. Increased PIK3CA alterations and downregulation of SCGB2A1, the inhibitor of PI3K kinase, in hDNAmad+ tumors, might promote tumor growth/proliferation and stemness. In addition, the inactivation of aging drivers/tumor suppressors (TP53, RB1, and CDKN2A) while enhanced telomere maintenance occurred more frequently in hDNAmad+ tumors, which supports sustained tumor growth. Prominently, hDNAmad+ tumors were featured with immunoexclusion microenvironments, accompanied by significantly higher levels of VTCN1 expression while lower PD-L1 and CTLA4 expression, which indicates their poor response to immune checkpoint inhibitor (ICI)-based immunotherapy. We further showed significantly higher levels of DNMT3A and 3B expression in hDNAmad+ than in hDNAmad- tumors. Thus, the tumor suppressive function of aging-like DNA hypomethylation is severely impaired in hDNAmad+ tumors, likely due to enhanced expression of DNMT3A/3B and dysregulated aging regulators. Our findings not only enrich biological knowledge of EC pathogenesis but also help improve EC risk stratification and precision ICI immunotherapy.

Integrating single-cell RNA-seq and spatial transcriptomics reveals MDK-NCL dependent immunosuppressive environment in endometrial carcinoma

ObjectivesThe tumor microenvironment (TME) play important roles in progression of endometrial carcinoma (EC). We aimed to assess the cell populations in TME of EC.MethodsWe downloaded datasets of single-cell RNA-seq (scRNA-seq) and spatial transcriptome (ST) for EC from GEO, and downloaded RNA-Seq (FPKM) and clinical data of TCGA-UCEC project from TCGA. The datasets were analyzed using R software.ResultsWe obtained 5 datasets of scRNA-seq, 1 of ST and 569 samples of RNA-seq. Totally, 0.2 billion transcripts and 33,408 genes were detected in 33,162 cells from scRNA-seq. The cells were classified into 9 clusters, and EC cells were originated from epithelial cells and ciliated cells. Gene set variation analysis (GSVA) indicated that the pathways enriched in the subclusters of epithelial cells and endothelial cells were significantly different, indicating great heterogeneity in EC. Cell-cell communication analyses showed that EC cells emitted the strongest signals, and endothelial cells received more signals than other cells. Further analysis found that subclusters of 1 and 2 of epithelial cells were showed a more malignant phenotype, which may confer malignant phenotype to subcluster of 0 of endothelial cells through MK pathway by MDL-NCL signal. We also analyzed communications between spatial neighbors with ST data and confirmed the findings on MDL-NCL in cell-cell communication. TCGA and GEO analyses indicated that the expression levels of NCL was inversely correlated with ImmuneScore.ConclusionOur study revealed EC cells can confer malignant phenotype to endothelial cells by MDK-NCL signal, and NCL is associated with suppressed immune activity. EC cells may shape TME by inhibiting immune cells and “educating” stromal cells via MDK-NCL signal.

Loss of NLRP3 reduces oxidative stress and polarizes intratumor macrophages to attenuate immune attack on endometrial cancer

IntroductionThe interaction between endometrial cancer (EMC) cells and intratumoral macrophages plays a significant role in the development of the disease. PYD domains-containing protein 3 (NLRP3) inflammasome formation triggers caspase-1/IL-1β signaling pathways and produces reactive oxygen species (ROS) in macrophages. However, the role of NLRP3-regulated ROS production in macrophage polarization and the subsequent growth and metastasis of EMC remains unknown.MethodsWe conducted bioinformatic analysis to compare NLRP3 levels in intratumoral macrophages from EMC and normal endometrium. In vitro experiments involved knocking out NLRP3 in macrophages to shift the polarization from an anti-inflammatory M1-like phenotype to a proinflammatory M2-like phenotype and reduce ROS production. The impact of NLRP3 depletion on the growth, invasion, and metastasis of co-cultured EMC cells was assessed. We also evaluated the effect of NLRP3 depletion in macrophages on the growth and metastasis of implanted EMC cells in mice.ResultsOur bioinformatic analysis showed significantly lower NLRP3 levels in intratumoral macrophages from EMC than those from normal endometrium. Knocking out NLRP3 in macrophages shifted their polarization to a proinflammatory M2-like phenotype and significantly reduced ROS production. NLRP3 depletion in M2-polarized macrophages increased the growth, invasion, and metastasis of co-cultured EMC cells. NLRP3 depletion in M1-polarized macrophages reduced phagocytic potential, which resulted in weakened immune defense against EMC. Additionally, NLRP3 depletion in macrophages significantly increased the growth and metastasis of implanted EMC cells in mice, likely due to compromised phagocytosis by macrophages and a reduction in cytotoxic CD8+ T cells.DiscussionOur results suggest that NLRP3 plays a significant role in regulating macrophage polarization, oxidative stress, and immune response against EMC. NLRP3 depletion alters the polarization of intratumoral macrophages, leading to weakened immune defense against EMC cells. The reduction in ROS production by the loss of NLRP3 may have implications for the development of novel treatment strategies for EMC.

A novel necroptosis-related lncRNA signature for predicting prognosis and anti-cancer treatment response in endometrial cancer

BackgroundNecroptosis, a form of programmed cell death, underlies tumorigenesis and the progression of cancers. Anti-cancer strategies targeting necroptosis have increasingly been shown to present a potential cancer therapy. However, the predictive utility and anticancer sensitivity value of necroptosis-related lncRNAs (NRLs) for endometrial cancer (EC) are currently unknown.MethodsEC patient gene expression profiles and the corresponding clinical information collected from The Cancer Genome Atlas were used to identify NRLs that constituted a predictive signature for EC. The functional pathways, immune status, clinicopathological correlation, and anticancer drug sensitivity of the patients relative to the NRLs signatures were analyzed.ResultsA signature composed of 7 NRLs (AC019080.5, BOLA3-AS1, AC022144.1, AP000345.2, LEF1-AS1, AC010503.4, and RPARP-AS1) was identified. The high-risk patient group with this signature exhibited a poorer prognosis and lower survival rate than low-risk group lacking this signature. This necroptosis-related lncRNA signature had a higher predictive accuracy compared with other clinicopathological variables (area under the receiver operating characteristic curve of the risk score: 0.717). Additionally, when patients were stratified based on other clinicopathological variables, the overall survival was significantly shorter in the high-risk versus low-risk group across all cohorts. Gene set enrichment analysis (GSEA) revealed that immune- and tumor-related signaling pathways and biological processes were enriched in the high-risk group compared to the low-risk group. Single-sample gene set enrichment analysis (ssGSEA) additionally showed that the resulting risk score was strongly correlated with EC patient immune status. Finally, patients with high-risk scores were more sensitive to the anti-cancer drugs such as Docetaxel, Mitomycin.C, Vinblastine, AZD.2281 (olaparib), AZD6244, and PD.0332991 (Palbociclib).ConclusionThese findings reveal a novel necroptosis-related lncRNA signature for predicting EC patient prognosis and shed new light on anticancer therapy strategies for EC.

Deciphering comprehensive features of tumor microenvironment controlled by chromatin regulators to predict prognosis and guide therapies in uterine corpus endometrial carcinoma

BackgroundDysregulation of chromatin regulators (CRs) can perturb the tumor immune microenvironment, but the underlying mechanism remains unclear. We focused on uterine corpus endometrial carcinoma (UCEC) and used gene expression data from TCGA-UCEC to investigate this mechanism.MethodsWe used weighted gene co-expression network analysis (WGCNA) and consensus clustering algorithm to classify UCEC patients into Cluster_L and Cluster_H. TME-associated CRs were identified using WGCNA and differential gene expression analysis. A CR risk score (CRRS) was constructed using univariate Cox and LASSO-Cox regression analyses. A nomogram was developed based on CRRS and clinicopathologic factors to predict patients' prognosis.ResultsLower CRRS was associated with lower grade, more benign molecular subtypes, and improved survival. Patients with low CRRS showed abundant immune infiltration, a higher mutation burden, fewer CNVs, and better response to immunotherapy. Moreover, low CRRS patients were more sensitive to 24 chemotherapeutic agents.ConclusionA comprehensive assessment of CRRS could identify immune activation and improve the efficacy of UCEC treatments.

Case report: A successful re-challenge report of GLS-010 (Zimberelimab), a novel fully humanized mAb to PD-1, in a case of recurrent endometrial cancer

With the widespread use of immune checkpoint inhibitors (ICI), there is growing concern about reports of immune-related adverse events (irAE). In clinical practice, patients who experience severe toxicities by ICI-based therapies would require utmost caution in resuming ICI therapy because of the potential risk of serious irAEs caused by the reintroduction of immunotherapy. In this study, we report a case of recurrent endometrial cancer patient with PD-L1 positive as well as dMMR suffering from immunotherapy-associated myocarditis after first-line treatment with ICI combined with a multi-targeted anti-angiogenic agent. After symptomatic treatment, the patient was in complete remission from treatment toxicities. Subsequently, through MDT discussions, we selected a new PD-1 agent, zimberelimab, for rechallenge therapy, and the patient achieved a sustained disease remission without any treatment-related toxicities. To date, the manner and timing of the ICI re-challenge has been a subject of iterative deliberation. We believe that our experience could shed some light on ICI rechallenge therapy, and we look forward to more literatures to refine the ICI rechallenge scenarios.

Targeting immunometabolism mediated by the IDO1 Pathway: A new mechanism of immune resistance in endometrial cancer

Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called “kynurenine (Kyn) pathway”, which converts the essential amino acid l-tryptophan into the immunosuppressive metabolite l-kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.

Single-Cell RNA-Sequencing Atlas Reveals the Tumor Microenvironment of Metastatic High-Grade Serous Ovarian Carcinoma

Ovarian cancer is the most common and lethal gynecological tumor in women worldwide. High-grade serous ovarian carcinoma (HGSOC) is one of the histological subtypes of epithelial ovarian cancer, accounting for 70%. It often occurs at later stages associated with a more fatal prognosis than endometrioid carcinomas (EC), another subtype of epithelial ovarian cancer. However, the molecular mechanism and biology underlying the metastatic HGSOC (HG_M) immunophenotype remain poorly elusive. Here, we performed single-cell RNA sequencing analyses of primary HGSOC (HG_P) samples, metastatic HGSOC (HG_M) samples, and endometrioid carcinomas (EC) samples. We found that ERBB2 and HOXB-AS3 genes were more amplified in metastasis tumors than in primary tumors. Notably, high-grade serous ovarian cancer metastases are accompanied by dysregulation of multiple pathways. Malignant cells with features of epithelial-mesenchymal transition (EMT) affiliated with poor overall survival were identified. In addition, cancer-associated fibroblasts with EMT-program were enriched in HG_M, participating in angiogenesis and immune regulation, such as IL6/STAT3 pathway activity. Compared with ECs, HGSOCs exhibited higher T cell infiltration. PRDM1 regulators may be involved in T cell exhaustion in ovarian cancer. The CX3CR1_macro subpopulation may play a role in promoting tumor progression in ovarian cancer with high expression of BAG3, IL1B, and VEGFA. The new targets we discovered in this study will be useful in the future, providing guidance on the treatment of ovarian cancer.

Case report: A panorama gene profile of ovarian cancer metastasized to axillary lymph node

BackgroundOvarian cancer is among the most lethal gynecologic malignancies, with a high proportion of patients diagnosed at advanced stages, leading to poor survival outcomes. Axillary lymph node metastasis from ovarian cancer is extremely rare and the mechanism is still unclear.MethodsA comprehensive set of clinical and gynecologic oncology assessments were performed, including ultrasound, mammography, MRI, transvaginal ultrasound, and tissue staining. To unravel the carcinogenesis, the next-generation sequencing (NGS) was performed.ResultsConventional examinations and imaging suggested the presence of both occult breast cancer and ovarian cancer. However, immunohistochemical staining confirmed the diagnosis of high-grade serous ovarian carcinoma. Further analysis of NGS identified two novel missense mutations, D326E in BTK (Bruton’s tyrosine kinase) at SH2 domain and D251E in EPHA5 (EPH receptor A5), along with other known cancer- associated mutations. These mutations, particularly the novel missense mutations, may lead to metastasis to the axillary lymph nodes and drug resistance. Therefore, based on these findings, the chemotherapy regimen was adjusted accordingly.ConclusionThis is the first report on the panorama gene profile of ovarian cancer metastasis to axillary lymph node and we found two novel mutations (BTK pD326E and EPHA5 pD251E). This study unraveled the potential mechanism of genetic mutation for tumor metabolism, drug resistance, and metastasis.

High-Grade Endometrial Stromal Sarcoma: Molecular Alterations and Potential Immunotherapeutic Strategies

Endometrial stromal tumor (EST) is an uncommon and unusual mesenchymal tumor of the uterus characterized by multicolored histopathological, immunohistochemical, and molecular features. The morphology of ESTs is similar to normal endometrial stromal cells during the proliferative phase of the menstrual cycle. ESTs were first classified into benign and malignant based on the number of mitotic cells. However, recently WHO has divided ESTs into four categories: endometrial stromal nodules (ESN), undifferentiated uterine sarcoma (UUS), low-grade endometrial stromal sarcoma (LG-ESS), and high-grade endometrial stromal sarcoma (HG-ESS). HG-ESS is the most malignant of these categories, with poor clinical outcomes compared to other types. With advances in molecular biology, ESTs have been further classified with morphological identification. ESTs, including HG-ESS, is a relatively rare type of cancer, and the therapeutics are not being developed compared to other cancers. However, considering the tumor microenvironment of usual stromal cancers, the advance of immunotherapy shows auspicious outcomes reported in many different stromal tumors and non-identified uterine cancers. These studies show the high possibility of successful immunotherapy in HG-ESS patients in the future. In this review, we are discussing the background of ESTs and the BCOR and the development of HG-ESS by mutations of BCOR or other related genes. Among the gene mutations of HG-ESSs, BCOR shows the most common mutations in different ways. In current tumor therapies, immunotherapy is one of the most effective therapeutic approaches. In order to connect immunotherapy with HG-ESS, the understanding of tumor microenvironment (TME) is required. The TME of HG-ESS shows the mixture of tumor cells, vessels, immune cells and non-malignant stromal cells. Macrophages, neutrophils, dendritic cells and natural killer cells lose their expected functions, but rather show pro-tumoral functions by the matricellular proteins, extracellular matrix and other complicated environment in TME. In order to overcome the current therapeutic limitations of HG-ESS, immunotherapies should be considered in addition to the current surgical strategies. Checkpoint inhibitors, cytokine-based immunotherapies, immune cell therapies are good candidates to be considered as they show promising results in other stromal cancers and uterine cancers, while less studied because of the rarity of ESTs. Based on the advance of knowledge of immune therapies in HG-ESS, the new strategies can also be applied to the current therapies and also in other ESTs.

Establishing a Prognostic Signature Based on Epithelial–Mesenchymal Transition-Related Genes for Endometrial Cancer Patients

BackgroundsEpithelial–mesenchymal transition (EMT) is a sequential process where tumor cells develop from the epithelial state to the mesenchymal state. EMT contributes to various tumor functions including initiation, propagating potential, and resistance to therapy, thus affecting the survival time of patients. The aim of this research is to set up an EMT-related prognostic signature for endometrial cancer (EC).MethodsEMT-related gene (ERG) expression and clinical data were acquired from The Cancer Genome Atlas (TCGA). The entire set was randomly divided into two sets, one for contributing the risk model (risk score) and the other for validating. Univariate and multivariate Cox proportional hazards regression analyses were applied to the training set to select the prognostic ERGs. The expression of 10 ERGs was confirmed by qRT-PCR in clinical samples. Then, we developed a nomogram predicting 1-/3-/5-year survival possibility combining the risk score and clinical factors. The entire set was stratified into the high- and low-risk groups, which was used to analyze the immune infiltrating, tumorigenesis pathways, and response to drugs.ResultsA total of 220 genes were screened out from 1,316 ERGs for their differential expression in tumor versus normal. Next, 10 genes were found to be associated with overall survival (OS) in EC, and the expression was validated by qRT-PCR using clinical samples, so we constructed a 10-ERG-based risk score to distinguish high-/low-risk patients and a nomogram to predict survival rate. The calibration plots proved the predictive value of our model. Gene Set Enrichment Analysis (GSEA) discovered that in the low-risk group, immune-related pathways were enriched; in the high-risk group, tumorigenesis pathways were enriched. The low-risk group showed more immune activities, higher tumor mutational burden (TMB), and higher CTAL4/PD1 expression, which was in line with a better response to immune checkpoint inhibitors. Nevertheless, response to chemotherapeutic drugs turned out better in the high-risk group. The high-risk group had higher N6-methyladenosine (m6A) RNA expression, microsatellite instability level, and stemness indices.ConclusionWe constructed the ERG-related signature model to predict the prognosis of EC patients. What is more, it might offer a reference for predicting individualized response to immune checkpoint inhibitors and chemotherapeutic drugs.

Development and Clinical Validation of Novel 8-Gene Prognostic Signature Associated With the Proportion of Regulatory T Cells by Weighted Gene Co-Expression Network Analysis in Uterine Corpus Endometrial Carcinoma

BackgroundUterine corpus endometrial carcinoma (UCEC) is a gynecological malignant tumor with low survival rate and poor prognosis. The traditional clinicopathological staging is insufficient to estimate the prognosis of UCEC. It is necessary to select a more effective prognostic signature of UCEC to predict the prognosis and immunotherapy effect of UCEC.MethodsCIBERSORT and weighted correlation network analysis (WGCNA) algorithms were combined to screen modules related to regulatory T (Treg) cells. Subsequently, univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses were used to identify the genes in key modules. The difference in overall survival (OS) between high- and low-risk patients was analyzed by Kaplan–Meier analysis. The Tregs-related risk signature (TRRS) was screened by uni- and multivariate Cox analyses. Afterward, we analyzed the expression difference of TRRS and verified its ability to predict the prognosis of UCEC and the effect of immunotherapy.ResultsRed module has the highest correlation with Tregs among all clustered modules. Pathways enrichment indicated that the related processes of UCEC were primarily associated to the immune system. Eight genes (ZSWIM1, NPRL3, GOLGA7, ST6GALNAC4, CDC16, ITPK1, PCSK4, and CORO1B) were selected to construct TRRS. We found that this TRRS is a significantly independent prognostic factor of UCEC. Low-risk patients have higher overall survival than high-risk patients. The immune status of different groups was different, and tumor-related pathways were enriched in patients with higher risk score. Low-risk patients are more likely take higher tumor mutation burden (TMB). Meanwhile, they are more sensitive to chemotherapy than patients with high-risk score, which indicated a superior prognosis. Immune checkpoints such as PD-1, CTLA4, PD-L1, and PD-L2 all had a higher expression level in low-risk group. TRRS expression really has a relevance with the sensitivity of UCEC patients to chemotherapeutic drugs.ConclusionWe developed and validated a TRRS to estimate the prognosis and reflect the immune status of UCEC, which could accurately assess the prognosis of patients with UCEC and supply personalized treatments for them.

Follicular Helper T-Cell-Based Classification of Endometrial Cancer Promotes Precise Checkpoint Immunotherapy and Provides Prognostic Stratification

Despite the fact that management of EC is moving towards four TCGA-based molecular classifications, a pronounced variation in immune response among these molecular subtypes limits its clinical use. We aimed to investigate the determinant biomarker of ICI response in endometrial cancer (EC). We characterized transcriptome signatures associated with tumor immune microenvironment in EC. Two immune infiltration signatures were identified from the TCGA database (n = 520). The high- and low-infiltration clusters were compared for differences in patient clinical characteristics, genomic features, and immune cell transcription signatures for ICI prediction. A Lasso Cox regression model was applied to construct a prognostic gene signature. Time-dependent receiver operating characteristic curve, Kaplan–Meier curve, nomogram, and decision curve analyses were used to assess the prediction capacity. The efficacy of potential biomarker was validated by the Karolinska endometrial cancer cohort (n = 260). Immune signature profiling suggested that T follicular helper–like cells (Tfh) may be an important and favorable factor for EC; high Tfh infiltration showed potential for clinical use in the anti-PD-1 treatment. A Tfh Infiltration Risk Model (TIRM) established using eight genes was validated, and it outperformed the Immune Infiltration Risk Model. The TIRM had a stable prognostic value in combination with clinical risk factors and could be considered as a valuable tool in a clinical prediction model. We identified CRABP1 as an individual poor prognostic factor in EC. The Tfh-based classification distinguishes immune characteristics and predicts ICI efficacy. A nomogram based on Tfh-related risk score accurately predicted the prognosis of patients with EC, demonstrating superior performance to TCGA-based classification.

A Pan-Cancer Analysis of Tumor-Infiltrating B Cell Repertoires

Tumor-infiltrating B cells can play an important role in anti-tumor responses but their presence is not well understood. In this study, we extracted the B cell receptor repertoires from 9522 tumor and adjacent non-tumor samples across 28 tumor types in the Cancer Genome Atlas project and performed diversity and network analysis. We identified differences in diversity and network statistics across tumor types and subtypes and observed a trend towards increased clonality in primary tumors compared to adjacent non-tumor tissues. We also found significant associations between the repertoire features and mutation load, tumor stage, and age. Our V-gene usage analysis identified similar V-gene usage patterns in colorectal and endometrial cancers. Lastly, we evaluated the prognostic value of the repertoire features and identified significant associations with survival in seven tumor types. This study warrants further research into better understanding the role of tumor-infiltrating B cells across a wide range of tumor types.

Blocking of EphA2 on Endometrial Tumor Cells Reduces Susceptibility to Vδ1 Gamma-Delta T-Cell-Mediated Killing

BackgroundEndometriosis is a common gynecological disease characterized by the presence of endometrial tissue outside the uterus causing chronic inflammation, severe pain, and infertility. However, the innate immunity of gamma-delta (γδ) T lymphocytes in endometriosis has not been characterized. Women with endometriosis present numerous endocrine and immune dysfunctions and elevated risk for endometrial, ovarian, and breast cancers. The tyrosine kinase EphA2 is often overexpressed in cancer including endometrial carcinoma.MethodsWe analyzed Vδ1 and Vδ2 γδ T cells in peripheral blood and paired peritoneal fluid samples in endometriosis patients (n = 19) and compared the counts with that of age- and sex-matched healthy donors (n = 33) using flow cytometry. Vδ1 and Vδ2 T cells isolated from healthy donors were used against KLE, RL-95, and Ishikawa endometrial tumor cells in 4 h flow cytometric cytotoxicity assays. The EphA2 blocking studies were performed using antibody, small-molecule inhibitor ALW-II-41-27, and the CRISPR/Cas9.ResultsWe determined Vδ1 T cells substantially reduced in patients’ peripheral blood (p < 0.01) and peritoneal fluid (p < 0.001). No differences were found for circulating Vδ2 T cells compared with peritoneal fluid samples. We observed inherent cytotoxic reactivity of Vδ1 and Vδ2 γδ T lymphocytes against endometrial tumor cells. Importantly, we found reduced specific lysis of EphA2-positive cell lines KLE and RL-95 by Vδ1 T cells in the EphA2 antibody blocking studies and by the EphA2 inhibitor. Furthermore, Vδ1 T-cell-mediated killing was significantly decreased in RL-95 cell EPHA2 knockout. Finally, potent cytolytic activity exerted by Vδ1 T cells was significantly reduced in EPHA2 knockouts in renal A-498 and colon HT-29 carcinoma cell lines.ConclusionsWe determined variable levels of Vδ1 and Vδ2 γδ T cells in endometriosis patients. We observed inherent cytotoxic reactivity of γδ T-cell subsets against endometrial cell lines. Specifically, we found that blocking of EphA2 expression resulted in significant inhibition of endometrial tumor killing mediated by Vδ1 γδ T cells. These results suggest that EphA2 is involved in tumor cell lysis and contributes to susceptibility to Vδ1 γδ T cells cytotoxic reactivity.

Endometrial Cancer Suppresses CD8+ T Cell-Mediated Cytotoxicity in Postmenopausal Women

Endometrial cancer is the most common gynecological cancer. To investigate how it suppresses host immune function, we isolated CD8+ T cells from endometrial endometroid carcinomas and adjacent non-cancerous endometrium and determined if the tumor environment regulates cytotoxic capacity. Endometrial carcinomas had increased numbers of CD8+ T cells compared to adjacent non-cancerous endometrium. Tumor CD8+ T cells expressed significantly less granzyme A (GZA), B (GZB), and PD-1 than those in adjacent non-cancerous tissues and also had significantly lower cytotoxic killing of allogeneic target cells. CD103-CD8+ T cells, but not CD103+CD8+ T cells, from both adjacent and tumor tissue were primarily responsible for killing of allogeneic target cells. Secretions recovered from endometrial carcinoma tissues suppressed CD8+ cytotoxic killing and lowered perforin, GZB and PD-1 expression relative to non-tumor CD8+ T cells. Furthermore, tumor secretions contained significantly higher levels of immunosuppressive cytokines including TGFβ than non-tumor tissues. Thus, the tumor microenvironment suppresses cytotoxic killing by CD8+ T cellsviathe secretion of immunosuppressive cytokines leading to decreased expression of intracellular cytolytic molecules. These studies demonstrate the complexity of CD8+ T cell regulation within the endometrial tumor microenvironment and provide a foundation of information essential for the development of therapeutic strategies for gynecological cancers.

Complete remission of recurrent human papillomavirus-associated cervical cancer managed with camrelizumab and nanoparticle albumin-bound paclitaxel as second-line treatment: a case report

Cervical cancer is the fourth most prevalent oncological condition affecting the global female population in 2022, considering both disease occurrence and fatality rates. Although surgical intervention is the curative approach for early stage cervical cancer, recurrent progression is associated with unfavorable clinical outcomes. The current therapeutic protocols outlined in the National Comprehensive Cancer Network Guidelines 4.2025 edition propose that for second-line or subsequent therapies of cervical carcinoma, prioritized protocols incorporate pembrolizumab administration specifically for patients demonstrating high tumor mutational burden characteristics, positive for programmed cell death ligand 1 expression, or exhibiting microsatellite instability-high/mismatch repair deficiency molecular profiles. Other proposed therapeutic approaches include bevacizumab, paclitaxel, and nanoparticle albumin-bound paclitaxel (nab-paclitaxel). To date, no standardized systemic combination protocol has been established for the management of recurrent/metastatic cervical carcinoma after first-line treatment. The clinical application of camrelizumab combined with nab-paclitaxel as a second-line intervention for recurrent human papillomavirus (HPV)-associated cervical cancer remains rare in existing medical literature. This case report documents complete remission achieved through second-line camrelizumab combined with nab-paclitaxel therapy in a 65-year-old Chinese female with recurrent HPV-associated cervical cancer with positive programmed cell death ligand 1 (PD-L1) in whom initial treatment failed. Clinical outcomes included the disease-free survival of 22 months, accompanied by the first progression-free survival (PFS1) of 10 months and the PFS2 of 58 months. The overall survival was recorded at 92 months. The patient continues to undergo active clinical surveillance. Our case report illustrates that second-line immunochemotherapy utilizing camrelizumab in combination with nab-paclitaxel exhibits notable efficacy and manageable safety profile.

Efficacy and safety of adding immune checkpoint inhibitors to standard chemotherapy or chemoradiotherapy for advanced or recurrent cervical cancer: a meta-analysis

Background Immune checkpoint inhibitors (ICIs) combined with standard chemotherapy (CT) or chemoradiotherapy (CRT) have shown promising results in recent randomized controlled trials (RCTs) for advanced or recurrent cervical cancer (CC). However, comprehensive evidence is needed to evaluate their efficacy and safety, particularly in the context of patient subgroups and immune response mechanisms. This meta-analysis aimed to synthesize data from RCTs and apply trial sequential analysis (TSA) to validate findings. Methods We systematically searched PubMed, Web of Science, Embase, and the Cochrane Library from database inception through 19 December 2025. RCTs that evaluated the efficacy and safety of ICIs combined with CT or CRT for advanced or recurrent CC were identified and relevant data were extracted. Meta-analyses were performed to pool hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS), and risk ratios (RRs) for objective response rate (ORR) and adverse events (AEs). TSA was applied to control the risk of false-positive and false-negative findings for outcomes including PFS, OS, ORR, any grade and grade 3–5 AEs. AEs were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5.0. Results 5 RCTs totaling 3302 patients with CC met the inclusion criteria. The pooled analysis revealed that compared with CT or CRT (with or without placebo) the addition of ICIs to CT or CRT significantly improved PFS (HR = 0.661, 95% CI: 0.599-0.731; 95% prediction interval [PI]: 0.541-0.811) and OS (HR = 0.664, 95% CI: 0.590-0.747; 95% PI: 0.562-0.785). TSA confirmed the robustness of these findings. While the pooled ORR showed a numerical increase (RR = 1.117, 95% CI: 1.035-1.205), the 95% PI (0.888-1.404) suggested limited robustness. Subgroup analyses showed that the PFS and OS benefits were particularly pronounced in patients with a PD-L1 combined positive score (CPS) ≥ 1, while those with CPS <1 did not derive significant benefit. Safety analyses indicated that adding ICIs did not increase the risk of all-cause AEs of any grade (RR = 1.002, 95% CI: 0.996-1.008; 95% PI: 0.991-1.012), but was associated with a higher incidence of grade 3–5 AEs (RR = 1.076, 95% CI: 1.032-1.123; 95% PI: 1.021-1.144). Conclusion Adding ICIs to CT or CRT significantly improves survival outcomes in advanced or recurrent CC, particularly in PD-L1-positive patients. However, the increased risk of grade 3–5 AEs underscores the need for vigilant toxicity monitoring and management. These findings highlight the potential of ICIs to enhance immune-mediated tumor control, offering a promising therapeutic option for selected patient populations.

Comparison of drug regimens for recurrent or metastatic cervical cancer: a systematic review and network meta-analysis

Background Cervical cancer is one of the most common cancers among women worldwide. For patients with recurrent or metastatic cervical cancer (R/MCC) after surgery or radiotherapy, drug therapy is the primary treatment modality. Currently, head-to-head comparison studies of different immune checkpoint inhibitors (ICI) combination regimens are lacking in clinical practice. This study aims to provide an indirect comparison of the relative efficacy of various drug regimens (including chemotherapy, targeted therapy, and immunotherapy) for R/MCC patients through a systematic review and network meta-analysis (NMA). Method The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines and systematically searched databases including PubMed, Web of Science, Embase and the Cochrane Library for randomized controlled trials (RCTs) comparing drug treatment regimens. The primary efficacy endpoint was overall survival (OS). Progression-free survival (PFS) was analyzed as a s econdary endpoint to provide additional evidence of clinical activity. We conducted the NMA using a Bayesian random-effects model, estimated the ranking of each treatment regimen via the Surface Under the Cumulative Ranking Curve (SUCRA), and performed a Frequentist NMA as a sensitivity analysis. Result A total of 15 RCTs involving 4,588 R/MCC patients were included. The NMA results for OS showed that ICI combination regimens (with or without bevacizumab) provided a significant benefit compared to backbone chemotherapy. Specifically, the regimen of pembrolizumab plus chemotherapy and bevacizumab showed the greatest potential for OS benefit (Frequentist HR: 0.45, 95%CI: 0.30–0.67 vs. cisplatin plus paclitaxel), ranking first by SUCRA (87%). Among traditional chemotherapy regimens, only the cisplatin plus paclitaxel regimen was significantly superior to single-agent cisplatin (Frequentist HR: 0.74, 95%CI: 0.59–0.93). The NMA results for PFS indicated that the cadonilimab plus chemotherapy regimen was the most outstanding (Frequentist HR: 0.46, 95%CI: 0.32–0.66 vs. cisplatin plus paclitaxel), ranking first by SUCRA (90%). The rankings of the treatment regimens were consistent across both Bayesian and Frequentist, suggesting strong robustness of the results. Conclusion ICI combination regimens (with or without bevacizumab) are likely the optimal choice for treating R/MCC patients. Pembrolizumab plus chemotherapy and bevacizumab is most likely to yield the OS benefit, and cisplatin plus paclitaxel remains the best backbone chemotherapy regimen for R/MCC. This study provides comprehensive indirect comparison evidence for clinicians in selecting R/MCC treatment strategies. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251180897 , identifier CRD42024604107.

Detection of human papillomavirus (HPV)-specific T cell response in women with low-grade cervical intraepithelial lesion and HPV vaccinated subjects

Background Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide and HPV-driven cervical cancers remain a major health concern. This study aimed primarily to develop a test for assessing and characterizing HPV-specific T-cell responses, in HPV-vaccinated women and women with cervical intraepithelial neoplasia (CIN)1. Methods T-cell responses against HPV-16 and 18 L1, E6, and E7 proteins were evaluated by flow cytometry with a 24h activation-induced marker (AIM) and a 7-day lymphoproliferation (LPR) assays in 18 vaccinated and 60 CIN1 women. HPV genotyping was performed on vaginal swab samples. Results LPR assay demonstrated higher sensitivity than AIM. T-cell response was mainly directed against L1 and was higher in CD4+ than CD8+ T cells. All vaccinated women exhibited CD4+ T-cell responses against HPV-16 and to a lesser extent HPV-18 L1. Among CIN1 patients, 46.6% and 33.3% showed HPV-16 and -18 L1-specific CD4+ responses, respectively, even when infected with other HPV strains. Responses were predominantly associated with TH1 and TH17 phenotypes. Conclusions The LPR assay is a sensitive tool for detecting HPV-specific T-cell responses. The presence of T-cell responses in CIN1 patients infected with non-16/18 HPVs suggests potential cross-reactivity among HPV genotypes.

LAG-3–associated CD8+ T-cell dysfunction in the cervical cancer tumor microenvironment

Introduction Cytotoxic T lymphocytes (CTLs, mainly CD8 + T cells) are the primary killer cells in the tumor microenvironment (TME). This study investigates the expression of LAG-3 in the TME of cervical cancer and its regulatory role in CD8 + T cell function. Methods Cervical tissue pathological sections and fresh cervical tissues were collected from patients with cervical cancer, patients with high-grade squamous intraepithelial lesion (HSIL), and patients who underwent hysterectomy for non-cervical diseases (without a history of other tumors). Immunohistochemistry, Western blotting, quantitative real-time PCR, and fluorescence imaging techniques were used to analyze the expression of LAG-3 in the cervical cancer TME and its correlation with clinical tumor stage, differentiation grade, lymph node metastasis status, and lymphovascular space invasion. A cell co-culture system and a cervical cancer mouse model were established to evaluate the effects of lag-3 on tumor growth and changes in CD8 + T cell function. Results LAG-3 is highly expressed in the tumor microenvironment (TME) of cervical cancer, with its expression level increasing as the tumor stage progresses: the lower the degree of differentiation, the higher the LAG-3 expression; LAG-3 expression is also elevated in cases with lymph node metastasis and lymphovascular space invasion. In vivo mouse models confirmed that lag-3 inhibits CD8 + T cells from expressing Ki67, T-bet, TNF-α, IFN-γ, and IL-2. Furthermore, we found that lag-3 not only suppresses the differentiation of naive CD8 + T cells into central memory T cells (TCM) but also inhibits the differentiation of TCM into effector memory T cells (TEM), a subset with stronger anti-tumor effector functions. A similar phenomenon was observed in cell co-culture experiments. Discussion We confirmed that LAG-3 is highly expressed in cervical cancer tissues and is closely correlated with clinical stage, differentiation grade, lymph node metastasis, and lymphovascular space invasion. LAG-3 may inhibit the function of CD8 + T cells in the cervical cancer TME, thereby promoting the progression of cervical cancer.

A machine learning approach to a nine-SNP immunogenetic score for prognostic stratification in cervical cancer

Background While human papillomavirus (HPV) is the primary driver of cervical cancer (CC), host immune-related genetic variations are thought to influence clinical heterogeneity. The role of combined immune-related single nucleotide polymorphisms (SNPs) in defining patient subgroups remains underexplored in focused, candidate-gene studies. Methods We genotyped nine functional SNPs across TNF-α (rs361525, rs1800629), *IL-1β* (rs16944), IFN-γ (rs2430561), *IL-1RN* (rs2234663), *IL-10* (rs3024490, rs1800872, rs1800871), and *IL-6* (rs1474348) in a cohort of 130 Tunisian CC patients. Principal component analysis (PCA), multi-dimensional scaling (MDS), K-means clustering, and random forest modeling were used to explore SNP-based patient subgroups and identify genetic profiles associated with survival. Results A high-risk genetic profile, comprising seven SNPs, was identified in 20% of patients. PCA indicated that *IL-10* and TNF-α variants accounted for 38.5% of the observed genetic variance. Unsupervised clustering suggested three distinct SNP-based subgroups with differing genetic architectures. The TNF-α –238 A allele was associated with borderline higher odds of adenocarcinoma (OR 4.57, 95% CI: 0.95–21.95, p=0.050), while the *IL-1β* –511 T allele appeared protective (OR 0.45, 95% CI: 0.19–1.07, p=0.049). Random forest analysis identified the IFN-γ rs2430561 variant as the top predictor of advanced FIGO stage. A nine-SNP polygenic risk score (PRS) was significantly associated with reduced overall survival (HR 2.45, log-rank p<.001) and remained an independent prognostic factor in multivariable analysis. Pathway analysis implicated TNF-α signaling, IL-10 anti-inflammatory, and IL-1 cytokine pathways. Conclusions This focused, candidate-gene analysis identifies prognostic SNP-based subgroups and a nine-SNP polygenic risk score associated with survival in cervical cancer. While this work provides a foundation for immunogenetic risk stratification, the findings are derived from a limited SNP panel in a single cohort. Future validation in larger, independent cohorts with genome-wide data is required to confirm these preliminary genetic associations and to determine their relationship to broader molecular subgroups.

Nocardia rubra cell wall skeleton-induced MARCO expression: implications for improved phagocytosis and cytokine secretion in tumor-associated macrophages

Introduction Nocardia rubra cell wall skeleton (Nr-CWS) demonstrates a significant therapeutic effect against human papillomavirus (HPV) infection, but its precise immunomodulatory mechanisms warrant further investigation. This study investigates how Nr-CWS influences tumor-associated macrophages (TAMs) immune functions through macrophage receptor with collagenous structure (MARCO)-mediated mechanisms. Methods Cervical tissues of three cervical intraepithelial neoplasia (CIN) patients receiving Nr-CWS monotherapy and HPV infection turning negative were collected before and after treatment, and gene microarray analysis was performed. MARCO expression and immune cell infiltration were further analyzed using transcriptomic data from 33 tumor types in The Cancer Genome Atlas (TCGA). In vitro, TAMs derived from Human Monocytic Leukemia Cell Line 1 (THP-1) cells were treated with Nr-CWS, and changes in MARCO expression, cytoskeletal rearrangement, pseudopod length, lysosome count, and cytokine secretion were assessed. MARCO inhibition experiments were also performed. Results Gene microarray revealed significant upregulation of MARCO, a key phagosome pathway gene, post-treatment. TCGA analysis indicated that MARCO expression is significantly altered in most tumor tissues compared to normal tissues and is associated with the infiltration of multiple immune cell types, with a particularly strong correlation to macrophage abundance. Histologically, Nr-CWS increased MARCO⁺ macrophages in cervical tissues. In vitro , Nr-CWS elevated MARCO expression in TAMs, enhanced pseudopod formation, lysosome number, cytoskeleton reorganization, and promoted proinflammatory cytokine secretion. Conversely, MARCO inhibition suppressed these immune functions. Discussion The study demonstrates that Nr-CWS enhances TAM anti-tumor immune function via MARCO upregulation, leading to improved phagocytic activity and proinflammatory response. These findings align with genomic and cellular evidence, suggesting MARCO as a key mediator in Nr-CWS-induced macrophage reprogramming, with implications for HPV-related neoplasia immunotherapy.

Real-world data of cadonilimab in recurrent or metastatic cervical cancer in China: a multicentric study

BackgroundImmunotherapy has become a powerful clinical strategy for treating recurrent or metastatic cervical cancer (R/M CC). Cadonilimab, a novel anti-PD-1/CTLA-4 bispecific antibody, has shown substantial clinical benefits in cancer treatment. However, there is no real-world evidence of cadonilimab with a considerable sample size in R/M CC. Hence, we aim to assess the efficacy and safety of cadonilimab in R/M CC patients and explore its potential mechanism.MethodsThis retrospective real-world study examined a sample of R/M CC patients treated with cadonilimab at 13 large academic medical centers in China from July 6, 2022, to October 1, 2023. The outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), as well as safety profiles. Additionally, the programmed cell death 1 ligand 1 (PD-L1) was detected by immunohistochemistry to confirm its predictive values. Whole exome sequencing (WES) was also performed to investigate its potential antitumor mechanisms.ResultsAmong the 129 patients with measurable disease, the ORR was 38.8%, consisting of complete and partial responses in 8.5% and 30.2% of patients, respectively. The DCR was 72.1%. The median PFS was 12.4 months, while the median OS has not yet been reached. Subgroup analysis showed a numerical trend toward longer median PFS in patients with PD-L1 CPS ≥ 1 compared with CPS < 1 (14.0 vs. 12.8 months; P = 0.235). Moreover, combined therapy of cadonilimab and radiotherapy was identified as an independent prognostic factor for both OS and PFS. The most common grade 3 or worse adverse event was anemia (28 [20.1%]), decreased white blood cell count (24 [17.2%]), and decreased neutrophil count (20 [14.4%]). The most prevalent genetic variant was PIK3CA, highlighting the importance of the PI3K-AKT pathway in the antitumor mechanism of cadonilimab.ConclusionsCadonilimab shows an encouraging tumor response rate, with a manageable safety profile in patients with R/M CC. Notably, cadonilimab is also effective for those with PD-L1 CPS <1, suggesting a broad range of application prospects in R/M CC.Clinical Trial Registrationhttps://www.clinicaltrials.gov, identifier NCT06140589.

Efficacy and safety of Cadonilimab in the treatment of recurrent/metastatic and advanced cervical cancer: a systematic review and meta-analysis

Objective To investigate the efficacy and safety of Cadonilimab in patients with metastatic, recurrent, and advanced cervical cancer. Methods Computerized searches were performed in PubMed, Embase, Cochrane Library, Wiley Online Library, Web of Science, and the CBM database from their inception until October 4, 2025, to collect published studies on Cadonilimab for cervical cancer. A single-arm rate meta-analysis was conducted using R software (version 4.4.1) to evaluate outcome measures including efficacy, safety, and prognostic indicators. Results Ten studies involving 728 patients were included. The meta-analysis yielded the following pooled results: the overall response rate (ORR) was 57.8% (95% CI = 44.5%-70.2%), the disease control rate (DCR) was 81.8% (95% CI = 69.5%-89.9%), the complete response (CR) rate was 16.1% (95% CI = 10.2%-24.4%), and the partial response (PR) rate was 37.4% (95% CI = 28.6%-47.2%). The rates of stable disease (SD) and progressive disease (PD) were 19.8% (95% CI = 13.6%-27.9%) and 18.2% (95% CI = 10.1%-30.5%), respectively. The 6-month, 12-month, and 24-month overall survival (OS) rates were 78%, 78%, and 62%, respectively, while the 6-month and 12-month progression-free survival (PFS) rates were 53% and 48%, respectively. Regarding safety, the incidence of any-grade treatment-related adverse events (TRAEs) was 96.4% (95% CI = 75.5%-99.6%), the rate of grade ≥3 adverse events was 41.1% (95% CI = 25.2%-59.1%), and immune-related adverse events (irAEs) occurred in 38.6% (95% CI = 23.0%-56.9%) of patients. Conclusion This meta-analysis suggests that Cadonilimab is associated with antitumor activity and a manageable safety profile in patients with recurrent, metastatic, and advanced cervical cancer. Close monitoring for irAEs, vigilance against adverse events, and timely pharmacological intervention are essential during treatment to mitigate risks and achieve optimal therapeutic outcomes. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO , identifier CRD420251168672.

Comprehensive evaluation of prophylactic HPV vaccines: a systematic review and meta-analysis of efficacy, safety, and immunogenicity in males and females

Background Human papillomavirus (HPV) vaccination is a cornerstone of global strategies to prevent HPV-associated malignancies; however, uncertainties persist regarding its long-term efficacy, immunogenicity, and safety across populations, vaccine formulations, and dosing schedules. We conducted a comprehensive systematic review and meta-analysis to evaluate the clinical and immunological effectiveness of prophylactic HPV vaccines. Methods This study followed PRISMA guidelines and was registered in PROSPERO (CRD420251050526). Randomized controlled trials (RCTs) were identified through comprehensive searches of six major databases. Risk of bias was assessed using the RoB 2 tool. Meta-analyses were performed using random- or fixed-effects models as appropriate. Subgroup and meta-regression analyses explored the effects of age, sex, vaccine type, dosing regimen, and HIV status. Certainty of evidence was appraised using the GRADE framework. Results A total of 145 RCTs were included. HPV vaccination significantly reduced cervical intraepithelial neoplasia grade 1 (RR = 0.15, 95% CI: 0.09–0.24), grade 2 (0.20, 0.13–0.30), and grade 3 (0.48, 0.23–0.98). Persistent HPV16/18 infections were reduced by 84% (0.16, 0.12–0.21), and incident infections by 75% (0.25, 0.19–0.34). Immunogenicity analyses demonstrated robust antibody responses, with fold increases of 3.09 for HPV16, 3.10 for HPV18, 3.48 for HPV6, and 3.37 for HPV11. Tissue-resident CD4 + T cells were significantly reduced (SMD: −1.27, 95% CI: −2.24 to −0.31), while CD8 + T cells showed no significant change. Vaccination was not associated with an increased risk of serious adverse events (0.90, 0.82–0.99) or adverse pregnancy outcomes. Although, injection-site adverse events were modestly increased (1.26, 1.07–1.48). Conclusion Prophylactic HPV vaccination provides strong protection against HPV infections and precancerous lesions and induces robust humoral immunity with a favorable safety profile. The nonavalent vaccine, particularly when administered in a three-dose (0/1/6) regimen, offers the most comprehensive protection. These findings support the expansion of gender-neutral vaccination programs to maximize population-level cancer prevention. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420251050526.

Integration of histopathological images and immunological analysis to predict M2 macrophage infiltration and prognosis in patients with serous ovarian cancer

ObjectiveInvestigating the effect of M2 macrophage infiltration on overall survival and to use histopathological imaging features (HIF) to predict M2 macrophage infiltration in patients with serous ovarian cancer (SOC) is important for improving prognostic accuracy, identifying new therapeutic targets, and advancing personalized treatment approaches.MethodsWe downloaded data from 86 patients with SOC from The Cancer Genome Atlas (TCGA) and divided these patients into a training set and a validation set with a ratio of 8:2. In addition, tissue microarrays from 106 patients with SOC patients were included as an external validation set. HIF were recognized by deep multiple instance learning (MIL) to predict M2 macrophage infiltration via theResNet18 network in the training set. The final model was evaluated using the internal and external validation set.ResultsUsing data acquired from the TCGA database, we applied univariate Cox analysis and determined that higher levels of M2 macrophage infiltration were associated with a poor prognosis (hazard ratio [HR]=6.8; 95% CI [confidence interval]: 1.6–28, P=0.0083). External validation revealed that M2 macrophage infiltration was an independent risk factor for the prognosis of patients with SOC (HR=3.986; 95% CI: 2.436–6.522; P<0.001). Next, we constructed four MIL strategies (Mean probability, Top-10 Mean, Top-100 Mean, and Maximum probability) to identify histopathological images that could predict M2 macrophage infiltration. The Mean Probability Method was the most suitable and was used to generate a HIF model with an AUC, recall rate, precision and F1 score of 0.7500, 0.6932, 0.600, 0.600, and 0.600, respectively.ConclusionsCollectively, our findings indicated that M2 macrophage infiltration may increase prognostic prediction for SOC patients. Machine deep learning of pathological immunohistochemical images exhibited good potential for the direct prediction of M2 macrophage infiltration.

Cadonilimab rechallenge in patients with recurrent or metastatic cervical cancer following prior PD-1/PD-L1 inhibitor failure: a retrospective multicenter study

Purpose Patients with recurrent or metastatic cervical cancer (R/M CC) who progress after immunotherapy face limited treatment options. This study aimed to explore whether cadonilimab, a novel bispecific antibody targeting programmed cell death protein 1 (PD-1)/cytotoxic T-lymphocyte antigen-4 (CTLA-4), could effectively treat such patients following PD-1/programmed death-ligand 1 (PD-L1) inhibitor failure. Methods A retrospective multicenter study was conducted on 29 patients with R/M CC who received cadonilimab treatment after immune checkpoint inhibitor (ICI) failure between August 2022 and April 2024. The study assessed the objective response rate (ORR), the disease control rate (DCR), the progression-free survival (PFS), the overall survival (OS), and the safety profiles. Given the small sample size and its retrospective nature, this study is fundamentally descriptive, and its findings should be interpreted as exploratory. Results Among the 29 patients, the ORR was 24.1% (7/29) and the DCR was 55.2% (16/29). The median PFS was 5.8 months, while the median OS was 12.1 months. Subgroup analyses identified poorer prognoses for patients with liver metastasis, those with three or more prior treatment lines, and those receiving cadonilimab monotherapy. The most common grade 3 or higher adverse events (AEs) were anemia [8 (27.6%)], decreased white blood cell count [4 (13.8%)], and decreased neutrophil count [4 (13.8%)]. Conclusion Cadonilimab might offer a promising option with a manageable safety profile for patients with R/M CC who progress after ICI treatment. Further studies with larger sample sizes are needed to confirm these findings.

Immunohistochemical expression of IL-1β, IL-6, and NF-κβ in fibroids

Uterine fibroids are benign tumors that occur in a large proportion of women and interfere with the proper functioning of this organ. One of the factors leading to these proliferative changes appears to be the appearance of extracellular matrix (ECM) fibrosis at the site of local inflammatory foci. Due to the potential impact of cytokines in this process, it is interesting to determine their expression levels in fibroids and surrounding tissues, which may contribute to a better understanding of the mechanisms leading to the formation of these tumors. In tissue material from 50 women with uterine fibroids who underwent hysterectomy and 45 women operated on for other reasons (most often prolapse of the reproductive organ), the concentration of inflammatory cytokines IL-1β and IL-6 and the concentration of the transcription nuclear factor NF-κβ were determined. The tissue from the fibroid, the peripheral myometrium, and the unchanged myometrium were examined in women who underwent surgery for reasons other than uterine fibroids. A significant decrease in IL-1β levels was observed in the center of the fibroid compared to both peripheral and control muscle tissue (p=0.001). The concentrations of IL-6 were found to be similar across all three locations examined. The NF-κβ levels were significantly lower in the fibroid and peripheral tissues (p<0.001) compared to the control group. The concentration of IL-1β was found to be significantly and positively correlated with the concentration of NF-κβ in uterine fibroids.

Development and validation of immunotherapy nomogram for predicting the efficacy and prognosis of recurrent and metastatic cervical cancer

Background Cervical cancer, a major cause of cancer-related mortality in women, remains challenging to treat, particularly in recurrent or metastatic stages. Immunotherapy offers promise, but reliable biomarkers for predicting outcomes are lacking. Method A cohort of 204 patients with recurrent or metastatic cervical cancer who underwent immunotherapy was included in the study. Predictive factors were identified using LASSO regression combined with multivariate Cox proportional hazards analysis. Nomograms for progression-free survival (PFS) and overall survival (OS) were constructed by incorporating significant prognostic variables. Internal validation was performed via bootstrap resampling, and clinical applicability was assessed through decision curve analysis (DCA). Risk stratification was evaluated using Kaplan-Meier survival curves, with log-rank tests for comparison. In addition, to enhance the clinical applicability of the model, we downloaded external multi-center validation datasets from public databases, including TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus). Data from 306 cervical cancer patients were obtained and used as an independent validation cohort. These external datasets allowed for the verification of the developed model, ensuring its robustness and generalizability across different clinical settings. Results The analysis identified several significant prognostic factors for PFS, including histological type, maximum lesion diameter, CA125 levels, albumin concentration, lactate dehydrogenase (LDH) activity, and neutrophil-to-lymphocyte ratio (NLR). For OS, independent factors included BMI, liver metastasis, CEA levels, hemoglobin concentration, albumin levels, and LDH. The nomogram models demonstrated strong predictive accuracy, with concordance indices (C-index) of 0.706 for PFS and 0.769 for OS. Calibration curves indicated that the predicted and actual outcomes were in excellent agreement. The area under the curve (AUC) values for PFS at 1- and 2-year follow-up were 0.804 and 0.822, respectively, while for OS, the AUC values were 0.880 and 0.781. The risk stratification based on the nomogram scores revealed significant survival differences between high- and low-risk patients, with the high-risk group exhibiting poorer survival outcomes. External validation using data from the TCGA and GEO cohorts confirmed the robustness and generalizability of the nomogram models, further supporting their clinical relevance. Conclusion These nomograms provide a reliable tool for predicting outcomes in cervical cancer immunotherapy, helping to personalize treatment and improve clinical management, especially for metastatic disease.

CD155-based chimeric antigen receptor T cells: a promising immunotherapy for cervical and breast cancer

Introduction As an immune checkpoint molecule that is overexpressed in cervical and breast cancer, CD155 represents an attractive target for chimeric antigen receptor (CAR) T-cell therapy. However, it is crucial to thoroughly assess the efficacy and safety of CD155-based CAR T cells in preclinical models before considering clinical translation. Methods In this study, we developed a CD155-based CAR comprising the extracellular domain of the human TIGIT, 4-1BB, and CD3z signaling domains and utilized a murine model of cervical and breast cancer to comprehensively evaluate the antitumor responses elicited by the CD155-based CAR T cells. The CAR construct was specifically designed to recognize and target CD155-expressing tumor cells. Results The results of our study indicated that CD155 exhibits positive staining in the majority of clinical cervical and breast cancer tissues while showing no or low staining in normal tissues. In addition, we observed a correlation between the expression level of CD155 and the proliferation of malignant tumor cells. CD155-based CAR T cells effectively recognize and eliminate CD155-expressing tumor cells in vitro . Moreover, in vivo experiments using a murine model of cervical and breast cancer revealed that the administration of these CAR T cells leads to significant regression of established tumors without causing any observable toxicity. In addition, the clearance of CD155-positive tumor cells can effectively eliminate tumor cells that exhibit high proliferation rates. This suggests that the treatment approach may offer a safe and effective option for patients with cervical and breast cancer. Discussion Overall, our findings provide strong evidence for the efficacy and safety of CD155-based CAR T-cell therapy in cervical and breast cancer. This study contributes to the growing body of research supporting the potential clinical application of CD155-targeted immunotherapy for patients with cervical and breast cancer.

Successful sequential chemo-immunotherapy and reduced-volume brachytherapy for bulky residual cervical tumor after external beam radiotherapy: two case reports

Background Bulky residual tumor after external beam radiotherapy (EBRT) presents a major technical challenge for brachytherapy (BT) and is a significant prognostic risk factor in locally advanced cervical cancer (LACC). The use of chemotherapy combined with an immune checkpoint inhibitor to reduce tumor volume (TV) during the interval between EBRT completion and BT initiation has been rarely explored. Case description We present two cases of stage IIIC1r cervical squamous cell carcinoma with residual tumors larger than 5 cm following EBRT. Patient characteristics, examination findings, laboratory and imaging data, treatment responses, and adverse events were recorded. After sequential treatment with albumin-bound paclitaxel plus cisplatin combined with zimberelimab, both patients achieved marked tumor volume reduction and subsequently underwent reduced-volume BT. Neither patient experienced recurrence at 36-month and 25-month follow-ups, respectively. Conclusion Sequential chemo-immunotherapy followed by reduced-volume BT may represent an alternative treatment option for patients with bulky residual disease after EBRT. Further clinical studies are warranted to validate the effectiveness of this combined regimen.

Multi-omics reveals that NOTCH1 promotes cervical cancer progression and reduces radiosensitivity

Background Cervical cancer is the fourth most common malignancy in women globally. The NOTCH signaling pathway is aberrantly activated in multiple tumors, and NOTCH1, its core transmembrane receptor, is highly expressed in cervical cancer. However, NOTCH1’s mechanisms in cervical cancer progression and radiotherapy resistance, as well as its interaction with key molecules, remain unclear. Methods This study explored the role of NOTCH1 in cervical cancer from multi-omics perspectives, including single-cell sequencing, cDNA microarrays, high-throughput sequencing, and immunohistochemistry, combined with a series of in vitro and in vivo experiments. Results NOTCH signaling activity was negatively correlated with the overall survival and recurrence-free survival of cervical cancer patients. As the core molecule of this signaling pathway, NOTCH1 was significantly highly expressed in cervical cancer tissues and promoted cervical cancer cell proliferation in vitro. Single-cell analysis revealed that NOTCH1 was relatively highly expressed in CPA6+ and CEL+ malignant cells and involved in cell cycle regulation; further cell cycle detection assays confirmed that NOTCH1 could promote the G1-S phase transition. In addition, patients with high NOTCH1 expression showed decreased plasma cell infiltration in the microenvironment. Cell communication analysis indicated that malignant cells with high NOTCH1 expression might lead to impaired plasma cell differentiation due to the impairment of the MIF ligand-receptor pathway. Finally, NOTCH1 could reduce the radiosensitivity of cervical cancer cells to radiotherapy both in vitro and in vivo; whereas has-miR-449a, as an upstream regulatory miRNA of NOTCH1, could inhibit cervical cancer cell proliferation and enhance radiosensitivity by inhibiting NOTCH1 expression. Conclusions This study clarifies NOTCH1’s role in promoting cervical cancer progression and reducing radiosensitivity, with has-miR-449a as a negative regulator, providing targets for optimizing cervical cancer radiotherapy.

Microbiota–immune dysregulation in cervical cancer patients from Western Mexico: linking gut dysbiosis and NK cell exhaustion as promising biomarkers

Alterations in gut microbiota composition have been implicated in various diseases, including cancer. Recent evidence suggests that intestinal microbiota may influence the efficacy of immunotherapy. In this study, we investigated the relationship between gut dysbiosis and NK cell exhaustion in Mexican patients with cervical cancer (CC), a connection not previously explored. This cross-sectional study included newly diagnosed CC patients, a separate cohort of post-radio-chemotherapy (RCT) patients, and healthy donors (HD). Fecal microbiota profiles were assessed using 16S rRNA sequencing, while peripheral NK cell immune checkpoint expression was analyzed by multiparametric flow cytometry. CC patients exhibited significant gut dysbiosis, marked by reduced α-diversity, enrichment of pro-inflammatory taxa ( Escherichia - Shigella , Prevotella ), depletion of short-chain fatty acid (SCFA)-producing bacteria ( Ruminococcus , Christensenellaceae ), and enrichment of microbial metabolic pathways related to inflammation, oxidative stress, nutrient limitation, and immune suppression. Dysbiosis was more pronounced in patients after RCT, with further enrichment of Phascolarctobacterium . In parallel, NK cells displayed a putative exhausted phenotype, with elevated expression and co-expression of PD-1, LAG-3, TIM-3, TIGIT, BTLA, and NKG2A. A dysbiosis score and an NK exhaustion score were developed, revealing a significant positive correlation between microbial imbalance and NK cell exhaustion. Machine learning analysis identified the Escherichia / Ruminococcus ratio and PD-1 + CD56 bright NK cells as predictive markers of CC. Moreover, both dysbiosis and NK cell exhaustion markers were significantly associated with reduced patient survival. This is the first study to demonstrate a link between gut microbiota alterations and NK cell exhaustion in CC. Our findings suggest that gut dysbiosis may contribute to impaired anti-tumor immunity. This study supports the rationale for microbiota-targeted interventions as adjunctive strategies in CC, although prospective validation is required.

Cost-effectiveness analysis of cadonilimab plus bevacizumab and chemotherapy for persistent, recurrent, or metastatic cervical cancer

ObjectiveThe aim of this study is to investigate the cost-effectiveness of cadonilimab plus bevacizumab and chemotherapy in the first-line treatment for patients with persistent, recurrent, or metastatic cervical cancer from a healthcare system perspective in China.MethodsA partitioned survival model was established to estimate the total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) over a 10-year time horizon. Clinical data was sourced from the COMPASSION-16 trial; direct medical costs and utilities were obtained from a public drug bidding database and published literature. The robustness of the model was assessed via scenario, one-way and probabilistic sensitivity analyses.ResultsCadonilimab plus bevacizumab and chemotherapy yielded an additional cost of $31,654.02, with an additional QALY of 0.36, resulted in an ICER of $88,533.51/QALY compared with bevacizumab and chemotherapy. Utility values of progression-free survival (PFS), patient weight and price of cadonilimab were the most influential parameter on ICER. The probability of cadonilimab plus bevacizumab and chemotherapy being cost-effective was 0% at the WTP threshold of $38,042.49 per QALY. When the price of cadonilimab reduced by 72%, cadonilimab plus bevacizumab and chemotherapy would represent an economically viable treatment regime.ConclusionCadonilimab plus bevacizumab and chemotherapy may not be a cost-effective option as the first-line treatment in persistent, recurrent, or metastatic cervical cancer.

Multi-omics analyses construct an inflammatory response based prognostic gene signature for cervical cancer and suggest tumor infiltrating monocytes subgroups as key players

BackgroundInflammatory response in the tumor micro-environment contributes to the progression and treatment response of various types of cancers. However, for cervical cancer, a type of cancer initiated by the infection of HPV, the clinical relevance of the inflammatory response and the underlying mechanisms remain to be elucidated.MethodsThe RNA-seq and clinical data of cervical cancer patients in several public datasets was used to construct and validate a prognostic gene signature based on the inflammatory response related genes. Risk stratification of patients was carried out according to this gene signature, and bioinformatic analyses were conducted to depict the immune landscape, identify the enriched biological pathways and predict patients’ treatment response. Single-cell and bulk RNA-seq data was jointly analysed to explore the underlying cellular and molecular mechanisms of the gene signature. The RNA-seq data of our own cohort and additional public datasets was used to further validate the findings made in this study.ResultsA prognostic gene signature consisting of 16 inflammatory response related genes was constructed and successfully validated on multiple testing datasets. Patients in the low-risk group defined by this gene signature had significantly better survival (hazard ratio [HR]=0.48, 95% Confidence Interval [CI]: 0.275-0.85; Multivariate analysis on the CGCI testing dataset). The two risk groups had different immune landscapes, enriched biological pathways and predicted sensitivity to chemo-, radio- and immune-therapy. Two subgroups of tumor infiltrating monocytes with possibly opposite functions might be actively involved in the inflammatory response. SERPINE1 and ITGA5 expressed on endothelial cells might have synergic effects and regulate the infiltration of monocytes and macrophages. Findings were successfully validated with our own RNA-seq data and on additional public datasets.ConclusionThe inflammatory response in the tumor micro-environment of cervical cancer, possibly jointly regulated by multiple TIM subgroups, is associated with the prognosis and treatment response of cervical cancer patients and may be potential treatment targets.

The role of cGAS-STING signaling in HPV infection and HPV-related cancers

Human papillomavirus (HPV) is a highly prevalent virus that primarily infects human epithelial cells, resulting in a significant health burden by causing conditions such as anogenital warts, cervical cancers, and head and neck squamous cell carcinoma. Although vaccination has been implemented for cancer prevention, a thorough understanding of anti-HPV immunity remains of critical importance for HPV-related disease management. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway forms a key signaling cascade within the innate immune system, which is activated by cytosolic DNA and functions through the production of type I interferon (IFN-I). Accumulating evidence indicates a correlation between the cGAS-STING pathway and HPV infection, as well as HPV-related malignancies, suggesting its potential as a promising therapeutic target. This review discusses the role of the cGAS-STING signaling pathway in HPV infection and HPV-related cancers, as well as potential therapeutic strategies that target this pathway.

Salvage sequential integrated boost radiotherapy followed by sintilimab–bevacizumab in cervical small-cell carcinoma with >10 brain metastases: A 3-year survivor case report

BackgroundCervical small cell carcinoma (CSCC) is a rare and highly aggressive malignancy with a poor prognosis. Brain metastases develop in 10–20% of patients, complicating clinical management and underscoring the need for effective therapeutic strategies.Case presentationA 54-year-old female with CSCC developed 16 isolated brain metastases during treatment. She responded markedly to whole-brain radiotherapy (WBRT) combined with sequential integrated boost radiotherapy (SEB). Although recurrence emerged outside the SEB field one year later, subsequent treatment with immune checkpoint inhibitors and antiangiogenic agents induced complete remission (CR), achieving a progression-free survival (PFS) of 16 months. Remarkably, the patient has achieved an overall survival of 3 years since the diagnosis of brain metastases, without significant treatment-related cognitive impairment, and remains in CR.ConclusionThe combination of WBRT and SEB improves metastatic dose coverage in CSCC patients with multiple brain metastases. Furthermore, combining immunotherapy with antiangiogenic therapy demonstrates significant efficacy against post-radiation intracranial recurrence, supporting a multimodal individualized approach for further study.

Predicting preoperative lymph node status in patients with cervical cancer: development of interpretable machine learning model and support for the biological plausibility

BackgroundLymph node metastasis serves as a crucial prognostic risk factor for patients with cervical cancer. Accurate prediction of lymph node metastasis is important in guiding treatment selection. Therefore, our primary objective is the development and validation of machine learning models for predicting lymph node metastasis; the secondary objective is to utilize the sequencing data to provide biological plausibility.MethodsThis study retrospectively included 292 cervical cancer patients and prospectively recruited 54 cervical cancer patients. Univariate and multivariate analysis were conducted to explore the risk factors associated with lymph node metastasis. Subsequently, cellular-level validation was performed using single cell RNA-sequencing data. The prognostic value of the risk factor was assessed through bulk RNA-sequencing analysis. Finally, patients were divided into train and retrospective test sets in a 7:3 ratio to develop five machine learning models, while using the prospective test set to validate the models. Additionally, the Shapley Additive Explanation method was employed to enhance the interpretability of the models’ decision processes.ResultsFederation of Gynecology and Obstetrics stage (2018), squamous cell carcinoma antigen, monocyte count and platelet count were found to be significantly correlated with lymph node metastasis. Meanwhile, monocyte count was a significant risk factor (OR=2.28, p < 0.05). Single cell RNA-sequencing analysis revealed an increase in monocytes at IIIC1 stage compared to IB and IIB stages. Monocytes were significantly associated with prognosis and lymph node metastasis in the bulk RNA-sequencing. Finally, we developed and validated five machine learning models for predicting lymph node metastasis. The NNET model stood for its ability to predict lymph node metastasis (train set AUC: 0.86; retrospective test set AUC: 0.79; prospective test set: 0.76). In the interpretability of machine learning models, Shapley Additive Explanation values demonstrated the concrete contribution of each feature within the NNET model.ConclusionsThis study investigated the notable association between monocyte count and lymph node metastasis, highlighting the importance of monocytes in cervical cancer via bulk RNA-sequencing and single cell RNA-sequencing analysis. The developed interpretable machine learning models effectively aid clinicians in decision-making processes. Additionally, the Shapley Additive Explanation method improved the applicability of these machine learning models in real world.

Thyroid disorders as predictors of cemiplimab efficacy in recurrent/metastatic cervical cancer: real-world evidence from Poland

IntroductionImmune checkpoint inhibitors have improved survival in patients with recurrent or metastatic cervical cancer (r/mCC), yet reliable predictors of treatment efficacy remain undefined. Immune-related adverse events (irAEs) have been suggested as potential predictors of response, but evidence in cervical cancer is limited.MethodsWe conducted an ambispective, multicenter observational study of 37 patients with r/mCC treated with cemiplimab within Poland’s national rescue access program. Baseline characteristics, treatment outcomes, and irAEs were analyzed. Survival outcomes were estimated using the Kaplan–Meier method and compared using Cox proportional hazards models. A p-value of <0.05 was considered statistically significant.ResultsAfter a median follow-up of 9.2 months, 17 episodes of irAEs were reported in 40.5% of patients (n=15), with thyroid disorders being the most common (n=11, 64.7%). Patients who developed ir-thyroid disorders had significantly longer progression-free survival (hazard ratio [HR]=0.2; 95% confidence interval [CI]: 0.07–0.6, p=0.004) and overall survival (HR=0.2; 95% CI: 0.05–0.9; p=0.04) compared to those without such events. Moreover, the objective response rate was notably higher in this group (45.5% versus 11.5%, p=0.04). Most irAEs were mild and manageable, with a median time to onset of two months after cemiplimab initiation.ConclusionsIr-thyroid disorders may indicate enhanced immune activation and represent a potential surrogate of cemiplimab efficacy in r/mCC, although validation in larger cohorts is required.

Profiling of immune cell subsets and functional characteristics of cervical cancer based on single cell RNA sequencing

IntroductionA comprehensive characterization of immune cells within the tumor microenvironment (TME) of cervical squamous cell carcinoma (CSCC) is essential to advance understanding of tumor biology and guide immunotherapy development.MethodsUsing single-cell RNA sequencing, we analyzed 14,441 immune cells isolated from tumor tissues and paratumor tissues of three CSCC patients. By integrating data on tumor suppressors, oncogenic factors, cytokines, and chemokines, we performed differential gene expression analyses across immune populations.ResultsThis analysis identified nine major immune cell subsets, including CD8+ T cells, regulatory T cells (Tregs), natural killer/T cells (NK/T cells), B cells, plasmacytoid dendritic cells (pDCs), and macrophages. Notably, elevated CCR7 expression in exhausted CD8+ T cells was associated with improved prognosis, suggesting it as a preliminary candidate for an immunoregulatory target that warrants further investigation. Additionally, CCL5 levels were elevated in Tregs, indicating a possible involvement in their recruitment to the tumor site that requires further validation. Furthermore, differential gene expression analysis identified candidate genes for further mechanistic investigation.DiscussionThis systematic comparison of the TME between tumor and paratumor tissues reveals dynamic changes in the immune landscape, providing insights and suggesting potential targets for further study to enhance understanding and treatment of CSCC.

Integrated multi-omics analysis of single-cell and spatial transcriptomics reveals distinct hpv-associated immune microenvironment features and prognostic signatures in cervical cancer

BackgroundCervical cancer (CC) is a highly heterogeneous malignancy primarily driven by persistent infection with high-risk human papillomavirus (HPV). However, comprehensive analyses of heterogeneity in the immune microenvironment, particularly its spatial heterogeneity, between HPV-positive and HPV-negative CC remain limited, despite their critical clinical significance.MethodsWe performed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) sequencing on collected cervical cancer samples, integrating scRNA-seq, ST, and bulk RNA-seq to analyze distinct cell subtypes and characterize their spatial distribution. Multiplex immunofluorescence analysis was further utilized to validate HPV status-specific expression patterns. Cox regression and LASSO regression analyses were used to identify the prognostic signature on the TCGA dataset.ResultsThrough integrative analysis, we found that HPV-positive samples demonstrated elevated proportions of CD4+ T cells and cDC2s, whereas HPV-negative samples exhibited increased CD8+ T cell infiltration. In HPV-positive CC, epithelial cells acted as primary regulators of cDC2s via the ANXA1-FPR1/3 pathway, with cDC2s subsequently modulating CD4+ T cells and interferon-related CD8+ T cell subtypes. In contrast, HPV-negative CC featured epithelial cells predominantly influencing monocytes and macrophages, which then interacted with CD8+ T cells. Notably, the MDK-LRP1 ligand-receptor interaction emerged as a potential key mechanism for recruiting immunosuppressive cells into CC tumors, fostering an immunosuppressive microenvironment. Further, we constructed a risk score model based on an epithelial cell-related signature (ERS), which was significantly associated with patient survival. Noteworthy variations were observed in immune cell infiltration and immune microenvironment among distinct risk groups.ConclusionBased on integrated multi-omics data, we precisely delineated the spatial transcriptional features of the tumor microenvironment in CC with different HPV statuses, including identifying distinct CD8+ T cell states and cell-cell communication. In addition, we developed an ERS closely associated with the immune environment and prognosis of CC. These results increase our understanding of the molecular mechanisms of cervical cancer under different HPV statuses and provide assistance for the precise treatment of cervical cancer.

Single-cell profiling delineates the tumor microenvironment and immunological networks in patient-derived uterine leiomyosarcoma

BackgroundUterine leiomyosarcoma (ULSA) is a highly aggressive gynecologic malignancy characterized by early metastasis, profound immunosuppression, and resistance to conventional therapies, including immune checkpoint blockade (ICB). The intricate tumor microenvironment (TME) and cellular heterogeneity driving its progression and therapy resistance remain poorly defined.MethodsWe performed single-cell RNA sequencing (scRNA-seq) on metastatic lesions (pelvic cavity, rectum, peritoneum, bladder) from a treatment-naïve ULSA patient and compared them to normal uterine myometrium, MMM (n=5). Integrated analyses included cellular composition mapping, copy number variation (CNV) assessment, pseudotemporal trajectory reconstruction, cell-cell communication inference, functional enrichment, and validation via multiplex immunofluorescence (mpIF). Survival correlations were assessed using the TCGA-SARC cohort.ResultsIn this study, the main finding is that the tumor microenvironment (TME) has a strong immunosuppressive effect. Firstly, its characteristic is exhausted CD8+T cells. This study found that as time progresses, the initial cell markers (CCR7, MAL) gradually disappear, while the exhaustion markers (LAG3, HAVCR2, TIGIT) are enriched. This is associated with poor prognosis. Secondly, the M2-polarized macrophages are mainly composed of M2-like tumor-associated macrophages (TAMs) with tumor-promoting characteristics (CD163, FTH1, FTL, TIMP1), and there is a polarization from M1 to M2. Finally, the immature, tumor-promoting N2 neutrophils (CD15+EDARADD+) enriched in the metastatic foci are associated with poor prognosis. The cell communication involves the interaction of MIF-(CD74+CD44) between T/B cells, as well as the role of the CXCL8 signaling axis in promoting angiogenesis, TAM polarization, and immunosuppression.ConclusionFor the first time, a comprehensive single-cell map of ULSA was constructed, depicting a metastasis-susceptible cell subset (U11-EDARADD) and an extremely immunosuppressed tumor microenvironment dominated by depleted CD8+T cells, M2 macrophages and N2 neutrophils. These features shed light on the underlying mechanisms of chemotherapy resistance and immunotherapy failure. The biomarkers identified here (EDARADD, CLDN10, TMIGD2) as well as the dysregulated pathways (TGF-β, angiogenesis, MIF signaling) provide possible targets for future development of combined immunotherapy strategies against this deadly disease.

A new strategy for the treatment of advanced ovarian cancer: utilizing nanotechnology to regulate the tumor microenvironment

Advanced ovarian cancer (AOC) is prone to recurrence, which can be attributed to drug resistance. Drug resistance may be related to the tumor microenvironment (TME), including the immune and non-immune TME. In the immune TME, the immune effector cells such as dendritic cells (DCs), M1-like tumor-associated macrophages (M1-TAMs), and T cells are inhibited. In contrast, immunosuppressive cells such as M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) are activated. These changes make it difficult to produce immune effects and affect the efficacy of chemo-immunotherapy. In the non-immune TME, mechanisms such as apoptosis inhibition, DNA damage response (DDR), and epithelial-mesenchymal transition (EMT) can promote tumor growth, metastasis, and drug resistance. Despite the challenges posed by the TME in the treatment of AOC, the unique biological advantages of nanoparticles (NPs) make it possible to regulate the TME. NPs can stimulate the immune responses of M1-TAMs, DCs, and T cells while reducing the infiltration of immune suppressive cells such as M2-TAMs and Tregs, thereby regulating the AOC immune TME. In addition, NPs can regulate the non-immune TME by reducing apoptosis in AOC cells, inhibiting homologous recombination (HR) repair, reversing EMT, and achieving the effect of reversing drug resistance. In summary, the application of NPs provides some new venues for clinical treatment in AOC.

Ferroptosis-immune crosstalk in cervical cancer: mechanisms and therapeutic implications

Cervical cancer remains a leading cause of cancer-related mortality in women worldwide, particularly in regions with limited access to screening and vaccination. While immunotherapy has shown promise in treating advanced cervical cancer, immune evasion mechanisms within the tumor microenvironment continue to limit therapeutic efficacy. Ferroptosis, a form of iron-dependent regulated cell death characterized by lipid peroxidation, has recently been recognized as a crucial regulator of tumor progression and immune modulation. Emerging evidence suggests that ferroptosis interacts with immune signaling pathways, contributing to immune suppression, antigen presentation defects, and the remodeling of the tumor immune microenvironment in cervical cancer. This review highlights the current understanding of ferroptosis-related mechanisms underlying immune evasion in cervical cancer, including alterations in ferroptosis regulators, redox imbalance, and ferroptosis-induced release of immunomodulatory molecules. We further explore how targeting ferroptosis may enhance anti-tumor immunity and overcome resistance to immunotherapy. Finally, we discuss recent advances in ferroptosis-based therapeutic strategies and identify future directions for integrating ferroptosis modulation into cervical cancer treatment.

Serum profiling of the antibody response to HPV in women with or without abnormal cervical cytology undergoing cervical cancer screening

IntroductionUnderstanding the humoral immune response to HPV is important for understanding the natural history of infection and developing biomarkers for early detection of cervical cancer. This has been technically limited by HPV type diversity and challenges of high-throughput protein expression and display. This study aimed to profile the humoral immune response to the proteomes of 12 HPV types in women with or without abnormal cervical cytology undergoing cervical cancer screening.MethodsTo detect serum antibodies (Abs) against HPV, we developed custom HPV high-density diffusion-free nucleic acid programmable protein arrays (HD-NAPPA) displaying the proteomes of 2 low-risk (HPV6 and 11) and 10 high-risk (HR) HPV types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52 and 58). Arrays were probed with sera from women undergoing screening for cervical cancer, with normal (n=82) or abnormal (n=54) cervical cytology. HPV DNA testing and typing were done on cytology samples from all participants using an assay that detects 37 HPV types.ResultsAbs to any HPV protein were detected in 47.6% (95% C.I.: 36.5-58.8%) and 40.7% (95% C.I.: 27.9-54.9%) of women with normal and abnormal cytology, respectively and in 44.9% (95% C.I.: 36.4-53.6%) of all women. HPV16 DNA was the most frequently detected type (36.8%, 95% C.I.: 27.4-47.4%), however, Abs against HPV16 were remarkably the least frequently detected (7.4%, 95% C.I.: 3.8-13.5%). The most frequently detected Abs were against L1, in 30.1% (95% C.I.: 22.7-38.7%) of all women (31.7% and 27.8% of women with normal and abnormal Pap, respectively). Abs against E1 and E4 were the most (in 24.3%, 95% C.I.: 17.5-32.5%) and least (13.2%, 95% C.I.: 8.2-20.4%) frequently detected E-Abs in all women, respectively. Among all subjects with antibodies to either L1 or L2, 39.0% (95% C.I.: 24.6-55.5%) of those with L1 antibodies and 51.9% (95% C.I.: 32.4-70.8%) of those with L2 antibodies were positive for the antigen from only one HPV type.ConclusionOur findings shed light on the kinetics of HPV-specific humoral immunity in women with normal or abnormal cervical cytology and highlight the need for comprehensive immune profiling in different health and disease stages.

HPV infection and the immune microenvironment in cervical cancer

Cervical cancer remains a leading cause of cancer-related mortality in women, particularly in low-resource settings, despite advances in treatment modalities. The tumor immune microenvironment (TME) plays a pivotal role in cervical cancer pathogenesis, progression, and therapeutic response, driven largely by persistent HPV infection and subsequent immune evasion mechanisms. Clinical evidence supports the efficacy of pembrolizumab in PD-L1–positive recurrent/metastatic disease, while combinatorial strategies show promise in overcoming resistance. However, challenges persist, including biomarker identification and management of immune-related adverse events. This review elucidates the dynamic interplay between HPV-mediated immune suppression and the TME, highlighting the roles of tumor-associated macrophages (TAMs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and exhausted lymphocyte subsets in fostering an immunosuppressive milieu. Overall, this review integrates current advances in tumor immunology and immunotherapy, providing a comprehensive framework for developing precision-based strategies to improve outcomes in cervical cancer.

T cell subsets in cervical cancer tumor microenvironment: advances and therapeutic opportunities

Cervical cancer is the third most common malignancy among Chinese women in both incidence and mortality. Its progression is closely linked to complex interactions among immune cells within the tumor microenvironment (TME). As key components of the immune landscape, different T cell subsets play diverse and dynamic roles in shaping tumor immunity. This review provides a comprehensive overview of the roles of various T cell subsets in the TME of cervical cancer, with a focus on their distribution, functional heterogeneity, dynamic balance, and variations across different pathological subtypes and disease stages. We also highlight the intricate crosstalk between T cells and other immune cells in the TME and discuss recent advances in T cell-related immunotherapies for cervical cancer, including immune checkpoint inhibitors and HPV-targeted vaccines. By elucidating the roles of distinct T cell subsets and relevant immunotherapeutic approaches within the TME, this review provides insights into potential therapeutic targets and approaches for improving cervical cancer treatment and patient outcome.

High-expression of BCL10 inhibits cell-mediated immunity within the tumor immune microenvironment

BackgroundB-cell lymphoma 10 (BCL10) is a key signaling molecule that plays a pivotal role in activating the NF-κB signaling pathway. However, it is unclear whether prolonged activation of BCL10 within tumors lead to T cell exhaustion and suppress immune responses against cancer.MethodsIn this study, through multi-layered bioinformatics analysis and experimental verification, the role of BCL10 on immune cells in the tumor immune microenvironment was systematically investigated. The correlation between BCL10 expression and infiltrated immune cells was analyzed by immune algorithms such as xCELL, CIBERSORT, QUANTISEQ and MCPcounter using TCGA and GTEx databases. Furthermore, single-cell RNA sequencing data of the cervical squamous cell carcinoma(CESC)microenvironment were analyzed using the GEO database. Moreover, an implanted CESC mice model was established, in which the expression and correlation of BCL10, NF-κB, and PD-1 in CD8+ T cells, as well as the proliferation and apoptosis of CD8+ T cells, were analyzed.ResultsIn silico analysis revealed that the upregulation of BCL10 in tumor immune microenvironment (TIME) was correlation with decreased infiltration of CD8+T cells, CD4+Th1 cells and NK T cells, and increased infiltration of Treg cells and CD4+Th2 cells in most tumors including CESC. In implanted CESC mice model, BCL10 expression was found upregulated in CD8+T cells, consequently activating the NF-κB signaling, and leading to upregulation of PD-1 expression, inhibiting proliferation of CD8+T cells, and promoting apoptosis of CD8+T cells.ConclusionsBCL10 is closely associated with immunosuppression across various tumor types. In CESC, chronic stimulation and over-activation by tumor antigens result in exhaustion of CD8+ T cells through the over-activation of the NF-κB signaling pathway and upregulation of PD-1 expression.

Revolutionizing cervical cancer treatment: single-cell sequencing of TSPAN1+ tumor EPCs and immune checkpoints to assess drug sensitivity and optimize therapy

BackgroundCervical cancer’s tumor microenvironment (TME) was composed of a diverse array of immune cells that significantly influence tumor progression and response to treatment. Recent advancements in multi-omics and single-cell sequencing had provided valuable insights into the cellular heterogeneity and immune landscape of the TME, revealing critical interactions that shape tumor behavior and therapy outcomes.MethodThis study used multi-omics and single-cell sequencing to explore the immune landscape, cellular heterogeneity, and drug sensitivity in cervical cancer, focused on tumor subtypes and their interactions with immune cells, and aimed to understand therapy responses.ResultsThe research presented a thorough single-cell analysis of cervical cancer, identified distinct tumor epithelial cell (EPC) subtypes, and explored their roles in tumor progression, immune evasion, and therapeutic response. It underscored the potential of tumor EPCs as valuable biomarkers for prognosis and as targets for personalized treatment approaches.ConclusionThe immune landscape of cervical cancer and its interaction with tumor endothelial progenitor cells played crucial roles in determining the tumor’s progression and response to therapy. The classification of tumor subtypes based on immune characteristics and drug sensitivity was critical for personalized treatment. The identification of TSPAN1 as key biomarkers provided insight into tumor biology and potential therapeutic targets. Our findings emphasized the need for combining immune checkpoint modulation with precise drug sensitivity analysis to optimize treatment strategies, particularly in advanced cervical cancer.

The diagnostic of PAX1 gene methylation in cervical lesions and its role in the triage of non-16/18 HR-HPV positive

ObjectiveThis study aims to systematically evaluate the application value of PAX1 gene methylation detection in cervical lesion screening and its potential advantages in the triage of non-16/18 high-risk human papillomavirus (HR-HPV) positive patients.Materials and methodsThis study enrolled 1,619 HPV-positive female patients who visited the Affiliated Hospital of Qingdao University from December 2023 to March 2025, with 989 patients ultimately meeting the inclusion criteria. All subjects underwent HPV-DNA testing, cytological examination, colposcopy, and PAX1 gene methylation detection, with results analyzed in conjunction with histopathological evaluations. HPV-DNA detection was performed using fluorescence quantitative PCR methodology capable of identifying 17 high-risk HPV genotypes. Cytological examination results were classified according to the International Society of Cytology standards. PAX1 gene methylation detection employed fluorescence quantitative PCR technology with ACTB as the internal reference gene, determining methylation levels through calculation of ΔCT values. Statistical analyses included ROC curve assessment of diagnostic performance, with intergroup comparisons conducted using one-way analysis of variance and Pearson’s chi-squared test.ResultsThe results demonstrated that PAX1 gene methylation detection showed significantly better diagnostic performance compared to cytological examination for the detection of CIN2+ and CIN3+ lesions. The AUC values for PAX1 gene methylation detection in diagnosing CIN2+and CIN3+ were 0.934 (95% confidence interval [CI]: 0.916–0.948) with sensitivity of 93.49% and specificity of 93.24%and0.875 (95% confidence interval [CI]: 0.853–0.895)with sensitivity of 95.31% and specificity of 79.77%. Among non-16/18 HR-HPV(in women positive for high-risk HPV types other than 16/18) positive patients, PAX1 gene methylation detection demonstrated higher sensitivity and specificity than cytological examination, enabling more accurate identification of patients requiring further intervention and reducing unnecessary colposcopy referrals. Furthermore, in HR-HPV positive patients with cytology results ≤ASCUS, PAX1 gene methylation detection significantly decreased colposcopy referral rates (22.29%), thus alleviating patients’ medical burden.ConclusionPAX1 gene methylation detection exhibits strong diagnostic efficiency for cervical lesions and holds significant value in triage diagnosis of non-16/18 HR-HPV positive.

The comparison of efficacy and safety between cadonilimab (PD-1/CTLA-4) and anti-PD-1 inhibitors in patients with recurrent or metastatic cervical cancer: a retrospective real-world study

IntroductionCadonilimab provides substantial clinical benefits in recurrent or metastatic cervical cancer (R/M CC) in several clinical trials and meeting abstracts. However, the efficacy of cadonilimab in patients with prior failure of anti- programmed death receptor-1 (PD-1) inhibitors, as well as a direct comparison of its efficacy and safety with anti-PD-1 inhibitors, has not been reported in real-world settings.MethodsWe conducted a retrospective study at our hospital, including two R/M CC patient cohorts. The first cohort consisted of 101 patients who received cadonilimab, either as monotherapy or in combination with other therapies, between July 1, 2022, and October 31, 2024. The second cohort comprised 201 patients who were treated with anti-PD-1 inhibitors (alone or in combination) but did not receive cadonilimab, between August 1, 2018, and March 31, 2024. In cadonilimab group, 4 patients received monotherapy, 13 patients received radiotherapy or surgery, 72 patients received concurrent chemotherapy, 57 patients received targeted therapy. Among anti-PD-1 group, 6 patients received monotherapy, 34 patients received radiotherapy or surgery, 127 patients received concurrent chemotherapy, 116 patients received targeted therapy. Clinicopathologic information, peripheral blood markers and treatment regimens were collected and analyzed to identify prognostic factors of cadonilimab through response rate comparison, as well as univariate, and multivariate analyses. The objective response rate (ORR) was compared between the cadonilimab and anti-PD-1 groups, stratified by PD-L1 expression. Safety data were also analyzed.ResultsThe cadonilimab group achieved an ORR of 59.41%, while the anti-PD-1 inhibitors group had an ORR of 44.28%. R/M CC patients with squamous cell carcinoma independently predicted prolonged progression-free survival (p=0.010). In patients with squamous cell carcinoma, the ORR was 60.32% in the cadonilimab group compared to 48.34% in the anti-PD-1 group. Cadonilimab was associated with a survival benefit in patients who had previously failed anti-PD-1 treatment (p=0.007), and showed a significantly higher ORR than anti-PD-1 inhibitors in patients with negative PD-L1 expression (69.23% vs 33.33%, p=0.033). The occurrence of immune related adverse events (irAEs) appeared to be associated with longer medication cycles, while severe adverse reactions were linked to shorter cycles. In addition, the cadonilimab group had a higher cumulative incidence of irAEs, including severe irAEs (12.87% vs. 1.99%, p=0.001), multi-organ irAEs, dyspnea and hypothyroidism than anti-PD-1 inhibitors group.ConclusionCadonilimab improved survival in R/M CC patients with previous anti-PD-1 treatment failure, achieving higher ORR in patients with negative PD-L1 expression compared to ati-PD-1 inhibitors. However, this benefit was associated with a notable increase in irAEs.

Research progress on tumor-infiltrating lymphocyte therapy for cervical cancer

Cervical cancer is a common malignant tumor in women, and human papillomavirus (HPV) infection is a major cause of cervical cancer. Tumor-infiltrating lymphocytes (TILs) are a heterogeneous group of lymphocytes primarily composed of T lymphocytes found within the tumor parenchyma and stroma. These cells can be isolated from tumor tissue, activated, expanded in vitro, and reinfused into the patient to exert an anti-tumor immune effect. As a form of personalized immunotherapy, TILs therapy has shown satisfactory efficacy and safety in advanced recurrent and metastatic cervical cancer, offering new hope to patients with advanced cervical cancer. However, TILs therapy for advanced cervical cancer still faces several limitations and challenges. This article reviews the process and latest developments in TILs therapy for advanced cervical cancer and discusses the challenges in the usage and prospects for this treatment.

The fading guardian: clinical relevance of TP53 null mutation in high-grade serous ovarian cancers

Backgroundwe evaluated the concordance between immunohistochemical p53 staining and TP53 mutations in a series of HGSOC. Moreover, we searched for prognostic differences between p53 overexpression and null expression groups.Methodspatients affected by HGSOC were included. For each case p53 immunohistochemical staining and molecular assay (Sanger sequencing) were performed. Kaplan-Meier survival analyses were undertaken to determine whether the type of TP53 mutation, or p53 staining pattern influenced overall survival (OS) and progression free survival (PFS).Results34 HGSOC were considered. All cases with a null immunohistochemical p53 expression (n=16) showed TP53 mutations (n=9 nonsense, n=4 in-frame deletion, n=2 splice, n=1 in-frame insertion). 16 out of 18 cases with p53 overexpression showed TP53 missense mutation. Follow up data were available for 33 out of 34 cases (median follow up time 15 month). We observed a significant reduction of OS in p53 null group [HR = 3.64, 95% CI 1.01-13.16].Conclusionimmunohistochemical assay is a reliable surrogate for TP53 mutations in most cases. Despite the small cohort and the limited median follow up, we can infer that HGSOC harboring p53 null mutations are a more aggressive subgroup.

The HPV viral regulatory mechanism of TLRs and the related treatments for HPV-associated cancers

Infection with human papillomavirus (HPV) typically leads to cervical cancer, skin related cancers and many other tumors. HPV is mainly responsible for evading immune tumor monitoring in HPV related cancers. Toll like receptors (TLRs) are particular pattern recognition molecules. When the body is facing immune danger, it can lead to innate and direct adaptive immunity. TLR plays an important role in initiating antiviral immune responses. HPV can affect the expression level of TLR and interfere with TLR related signaling pathways, resulting in sustained viral infection and even carcinogenesis. This paper introduces the HPV virus and HPV related cancers. We discussed the present comprehension of TLR, its expression and signaling, as well as its role in HPV infection. We also provided a detailed introduction to immunotherapy methods for HPV related diseases based on TLR agonists. This will provide insights into methods that support the therapeutic method of HPV related conditions with TLR agonists

Efficacy and safety of adding immune checkpoint inhibitors to first-line standard therapy for recurrent or advanced cervical cancer: a meta-analysis of phase 3 clinical trials

BackgroundImmune checkpoint inhibitors (ICIs) combined with standard therapy (ST) have emerged as a novel treatment strategy for recurrent or advanced cervical cancer (r/a CC). However, the available data from phase 3 clinical trials have yielded mixed results. This study aims to evaluate the therapeutic efficacy and safety of adding ICIs to ST in the treatment of r/a CC.MethodsData from four phase 3 clinical trials (KEYNOTE-826, CALLA, BEATcc, and ENGOT-cx11/GOG-3047/KEYNOTE-A18), involving 2,857 patients, were analyzed. Meta-analyses were conducted to combine hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), odds ratios (ORs) for the objective response rate (ORR), and relative risks (RRs) for adverse events (AEs).ResultsThe addition of ICIs to ST significantly improved PFS (HR, 0.67; 95% CI, 0.60-0.75), OS (HR, 0.66; 95% CI, 0.58-0.75), and ORR (OR, 1.48; 95% CI, 1.13-1.94) compared to ST alone. However, there was a modest increase in grade 3-5 AEs (RR, 1.08; 95% CI, 1.03-1.13) with the combined therapy.ConclusionThis meta-analysis indicates that the combination of ICIs with ST in the treatment of r/a CC not only demonstrates superior efficacy over ST alone but also maintains a comparable toxicity profile, offering strong evidence for an effective and relatively safe treatment approach for managing this disease.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024593895.

Gene expression levels associated with impaired immune response and increased proliferation could serve as biomarkers for women following cervical cancer screening programmes

Human papilloma virus (HPV) infections vary in their oncogenic potential, and whether an infection progresses to cervical intraepithelial neoplasia (CIN) also depends on the immune response. Therefore, the aim of the present study was to explore biomarkers related to the immune system and cell proliferation, in combination with HPV classified as having high (HOP) or low oncogenic potential (LOP), that can possibly guide a more accurate identification of women following cervical cancer screening programmes in need for immediate follow-up with a biopsy. A next-generation sequencing transcriptomic immune profile analysis applied to 28 persistent CIN3 lesions and 14 normal biopsies identified four genes, the immune markers ARG1 and HLA-DQB2 and the tumour markers CDKN2A and KRT7, as possible markers for differentiating between CIN3 and normal tissue. To validate these findings, analysis of the relative gene expression of these markers by use of reverse transcriptase real-time quantitative polymerase chain reaction was performed in an independent cohort of 264 (82 normal, 64 CIN1, and 118 CIN2/CIN3) biopsies, and the data were combined with information on the HOP- or LOP-HPV identified in the biopsies. Statistical analysis was performed with receiver operating characteristic curves, reporting area under the curve (AUC) with 95% confidence intervals (CIs), and logistic regression. Statistically significantly higher median expression levels of CDKN2A (p < 0.001) and KRT7 (p = 0.045) and significantly lower expression of ARG1 (p = 0.012) were found in biopsies with HOP-HPV infections, with no difference detected for HLA-DQB2 (p = 0.82). Models using expression levels of CDKN2A (AUC, 0.91; 95% CI, 0.86–0.95), KRT7 (0.86, 0.81–0.91), or ARG1 (0.78, 0.70–0.85) together with HOP/LOP-HPV class were significantly better than HPV class alone (0.72, 0.66–0.79) in discriminating CIN2/3 versus CIN1 (p < 0.001, p < 0.001, and p = 0.014, respectively).

Complete remission of a high-risk, locally advanced cervical cancer with para-aortic lymph node metastases treated with first-line tislelizumab plus bevacizumab combined with chemotherapy followed by radiotherapy with maintenance therapy: a case report

Newly diagnosed cervical cancer with metastatic para-aortic lymph node (PALN) involvement is associated with a significantly poor prognosis, with distant metastasis being the predominant pattern of treatment failure. The programmed cell death receptor-1 (PD-1) pathway has garnered considerable attention due to its role in enabling tumor cells to evade immune surveillance by eliciting the immune checkpoint response of T cells, rendering them highly refractory to conventional chemotherapy. The National Comprehensive Cancer Network (NCCN) guidelines currently recommend pembrolizumab for locally advanced cervical cancer patients positive for PD-L1 (CPS ≥1), as determined by an FDA-approved assay. Tislelizumab, an anti-PD-1 monoclonal IgG4 antibody, has been investigated in hematological malignancies and advanced solid tumors. Nevertheless, literature on regimens incorporating tislelizumab for the treatment of locally advanced cervical cancer is scarce. Herein, we present a case of a newly diagnosed high-risk, locally advanced cervical cancer patient with PALN metastases and low PD-L1 expression, treated with a combination of tislelizumab, bevacizumab, and a platinum-containing chemotherapy regimen followed by radiotherapy with maintenance therapy, resulting in a notable extension of progression-free survival.

Tissue-resident immune cells in cervical cancer: emerging roles and therapeutic implications

The favorable prognosis of “hot” tumors is widely acknowledged in oncology. Recently, the concept of tertiary lymphoid structures (TLS) has renewed appreciation for local immune cells within tumor tissues. Tissue-resident immune cells, a newly identified subset of tumor-infiltrating lymphocytes, are emerging as potential key players in tumor infiltration and TLS formation, due to their ability to reside indefinitely within tissues and mount effective responses to local antigens. Cervical cancer (CC), the fourth most common cause of cancer-related mortality among women globally, has experienced comparatively limited progress in delineating its tumor immune microenvironment compared to other malignancies. Notably, the role of tissue-resident immune cells within the CC milieu remains inadequately characterized. This comprehensive review aims to synthesize current knowledge and critically evaluate the putative roles of these cells in CC pathogenesis, providing new insights on the intricate dynamics of the local tumor microenvironment.

Cadonilimab plus chemotherapy as first-line treatment for persistent, recurrent, or metastatic cervical cancer: a cost-effectiveness analysis

BackgroundImmunotherapy has made significant advancements in cervical cancer (CC) treatment; however, its efficacy remains limited in programmed death ligand 1 (PD-L1)-negative patients. Cadonilimab, the first bispecific antibody targeting both programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), demonstrated superior efficacy and manageable safety as a first-line treatment for persistent, recurrent, or metastatic CC (p/r/m CC) in the phase III COMPASSION-16 trial. Notably, it showed significant survival benefits in PD-L1-negative patients. This study aimed to evaluate its cost-effectiveness from the perspective of the Chinese healthcare system.MethodsA partitioned survival model was developed based on data derived from the COMPASSION-16 trial. The model utilized a 3-week cycle length and a 10-year time horizon. The primary outcomes included costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net monetary benefit (INMB), and incremental net health benefit (INHB). Additionally, sensitivity analyses, scenario analyses, and subgroup analyses were performed.ResultsThe cadonilimab plus chemotherapy regimen provided an additional 0.61 QALYs compared to chemotherapy alone, at an incremental cost of $42,486.54. This yielded an ICER of $70,220.88/QALY, exceeding the willingness-to-pay threshold of $38,042/QALY. The corresponding INMB and INHB were -$19,469.55 and -0.51 QALYs, respectively. Consequently, cadonilimab plus chemotherapy was not deemed to be cost-effective. Sensitivity analyses showed that the results remained consistent when each parameter varied within the predetermined range, indicating the model’s robustness. Subgroup analyses demonstrated no significant positive correlation between economic outcomes and PD-L1 expression levels. Notably, in the subgroup of patients who did not receive bevacizumab, cadonilimab plus chemotherapy emerged as a cost-effective alternative.ConclusionIn China, cadonilimab plus chemotherapy is not considered cost-effective compared to standard chemotherapy as a first-line treatment for the general p/r/m CC population. However, it represents a cost-effective option for patients ineligible for bevacizumab therapy.

Epithelial and macrophage cell interaction in cervical cancer through single-cell RNA-sequencing and spatial analysis

BackgroundCervical cancer (CC) is a major global health issue, ranking sixth in cancer-related mortality. The tumor microenvironment (TME) plays a crucial role in tumor growth. This study explored the cellular composition and immunological landscape of CC using various genomic data sources.MethodsData from the Cancer Genome Atlas and Gene Expression Omnibus were analyzed, including single-cell RNA sequencing, spatial transcriptome analysis, and survival data. Gene set variation analysis (GSVA) identified pathways in CD8+ cells, macrophages, and epithelial cells. Immunohistochemistry assessed marker expression in CC and normal tissues. Tumor immune dysfunction and exclusion (TIDE) scores differentiated high- and low-macrophage groups. Cell–cell communication analyses highlighted interactions between macrophages and epithelial cells.ResultsMacrophage markers correlated with overall survival (OS) and disease-free survival (DFS). Epithelial cell subgroups 1 and 4, along with CD8+ T cells, were associated with OS. TIDE scores varied between groups. Specific ligand-receptor interactions were found between macrophages and epithelial cell subgroup 1. Triptolide was effective in epithelial cell subgroup 1, while memantine was more effective in macrophages.ConclusionEpithelial-macrophage interactions in the TME are crucial for CC progression and treatment, offering a potential immunotherapeutic strategy.

Effectiveness and safety of ICIs for the treatment of advanced CC: a systematic review and meta-analysis

BackgroundThe use of immune checkpoint inhibitors has recently become a promising and innovative therapeutic option for patients suffering from advanced recurrent or metastatic cervical cancer(CC), and several studies of immunotherapy have been published or have revealed stage-by-stage results at international congresses. Nevertheless, there is a lack of meta-analyses of ICIs for advanced CC in past Meta-analysis.MethodThis meta-analysis rigorously followed the PRISMA guidelines, using Review Manager V.5.4 and R(v4.2.2) software for data synthesis. Hazard ratios, risk ratios, and risk differences were calculated, with statistical significance assessed via the Mantel-Haenszel test. Heterogeneity was evaluated using the Higgins I2 statistic, and sensitivity analyses were conducted if heterogeneity surpassed 50%. The efficacy outcomes examined and gathered included the overall response rate (ORR), progress-free survival, overall survival(OS), and the adverse events (AEs), crucial for understanding the efficacy and safety of ICIs in advanced cervical cancer.ResultThe results demonstrate significant efficacy and manageable safety of ICIs in advanced cervical cancer. In RCTs, ICIs improved OS (HR = 0.66, 95% CI: 0.58-0.75, P < 0.00001) and PFS (HR = 0.67, 95% CI: 0.59-0.75, P < 0.0001), with a 34% and 33% reduction in death and progression risks, respectively. ORR was higher in ICIs groups (RR = 1.39, 95% CI: 1.08-1.80, P = 0.01). Single-arm studies supported these findings (ORR: RD = 0.31, 95% CI: 0.22-0.40, P < 0.0001). Safety profiles were manageable, with comparable TRAEs in RCTs and higher incidences in single-arm studies. Subgroup analysis revealed superior OS benefits in PD-L1-positive patients (CPS ≥1, HR = 0.65, 95% CI: 0.50–0.84, P = 0.001) and significant efficacy in squamous cell carcinoma (HR = 0.67, P < 0.00001). Sensitivity analysis confirmed robust OS results (I² = 0%) and stable ORR despite heterogeneity. Risk of bias was low to moderate.ConclusionOur meta-analysis reveals that immune checkpoint inhibitors (ICIs) significantly prolong overall survival in advanced cervical cancer patients, reducing the hazard ratio for death. Despite heterogeneity in outcomes, ICIs offer substantial treatment benefits. Further research is needed to optimize usage and monitor AEs.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier CRD42023387789.

Atezolizumab plus bevacizumab and chemotherapy as first-line therapy for cervical cancer: a cost-effectiveness analysis in the US

ObjectiveMedication is the predominant therapy for advanced cancers. However, the use of novel anticancer medications is a major contributor to disease-related financial hardships. Recently, numerous countries have mandated the pharmacoeconomic assessments of novel oncological agents to mitigate patient financial risks and optimize resource allocation. The present study evaluated the cost-effectiveness of adding atezolizumab to standard therapy (atezolizumab plus bevacizumab [BC]) for metastatic, persistent, and recurrent cervical cancer from the perspective of US healthcare payers, with the aim of supporting policymaking and promoting the rational use of healthcare resources.MethodsUsing clinical efficacy and safety data from the BEATcc clinical trial, in addition to cost and utility values from publicly available databases and published literature, a partitioned survival model over a 20-year lifetime horizon was developed to assess the cost-effectiveness of atezolizumab plus bevacizumab and chemotherapy (ABC) versus BC. The primary output of the model was the incremental cost-effectiveness ratio (ICER) and sensitivity analyses were performed to assess its robustness.ResultsAt both 20 and 4.5 y of time horizon, ABC therapy showed poor cost-effectiveness, with ICER of $193926.48/QALY and $168482.26/QALY, respectively, which were higher than the $150,000/QALY willingness-to-pay threshold. One-way sensitivity analysis showed that the price of atezolizumab had the most significant impact on the model results. When the price of atezolizumab was reduced by 10%, ABC changed from being not cost-effective to cost-effective (ICER = $121531.24/QALY). Probabilistic sensitivity analysis showed a 32.6% probability that ABC would be cost-effective, which increased to 58.6% when the price of atezolizumab was reduced by 10%.ConclusionsFor patients with metastatic, persistent, and recurrent cervical cancer in the US, ABC was not as cost-effective as BC. Appropriate price reduction (10%) is recommended for atezolizumab to improve cost-effectiveness of ABC therapy.

Case report: Cutaneous metastasis of squamous cervical carcinoma: complete regression after molecular diagnosis

Common metastasis sites for cervical cancer are the lungs, bones, liver, brain, ovaries, and lymph nodes, among other sites. Skin metastasis is very uncommon, and is only observed in approximately 1% of patients. The cancer spreads typically through lymphatic or blood vessels, but a definitive example of lymphatic spread has not been documented thoroughly in the existing literature. Cutaneous metastasis may be confused with cellulitis or a rash; hence, an immediate cutaneous biopsy of any suspicious lesions is recommended. There is no consensus regarding the treatment of this condition. Only one documented case has shown that a combination of paclitaxel, carboplatin, bevacizumab, and zoledronic acid can lead to a complete metabolic response. Our study, which used two cycles of albumin-bound paclitaxel, cisplatin, and bevacizumab, followed by four cycles of the same regimen plus terprelimab for metastases with CPS scores of Programmed death-ligand 1 (PD-L1) over 10, resulted in a stable complete response for over eight months. Our contribution may assist in formulating effective treatment guidelines for the cutaneous metastasis of squamous cervical carcinoma in the future.

Efficacy and safety of chemoradiotherapy plus immune checkpoint inhibitors for the treatment of locally advanced cervical cancer: a systematic review and meta-analysis

BackgroundRadiotherapy plus concurrent chemotherapy is a standard method for treating locally advanced cervical cancer (LACC). Immune checkpoint inhibitors (ICIs) are widely applied in the treatment of recurrent cervical cancer, metastatic cervical cancer or LACC. The efficacy and safety of radiotherapy plus immunotherapy for LACC require further investigation. The objective of this review and meta-analysis was to analyze the efficacy and safety of concurrent chemoradiotherapy (CCRT) combined with ICIs for treating LACC on the basis of the results of randomized controlled trials (RCTs).MethodsWe comprehensively searched electronic databases to identify RCTs that focused on CCRT plus ICIs for LACC treatment. The outcomes included the objective response rate (ORR) and progression-free survival (PFS), overall survival (OS) and adverse events (AEs). A standard method for systematic review and meta-analysis was used. Review Manager 5.4 was used for data combination and analyses.ResultsThree RCTs involving 1882 participants with LACC were identified and included in the systematic review and meta-analysis. CCRT plus ICIs improved the rates of PFS (hazard ratio [HR]: 0.76, 95% confidence interval [CI]: CI: 0.64, 0.91, P = 0.002) and OS (HR: 0.7695% CI (95% CI 0.58–0.99, P = 0.04) in patients with LACC. Compared with the control group, the CCRT plus immunotherapy group had an increased ORR (OR: 1.37, 95% CI: 1.02,1.85, P=0.04). The two methods had similar rates (HR=1.99, 95% CI: 0.99, 1.43; P=0.07) of treatment-related grade 3 or higher AEs. The CCRT plus immunotherapy group had a higher rate than did the control group (HR: 2.68, 95% CI: 1.38, 5.21; P=0.004) in terms of any grade immunotherapy-related AEs.ConclusionsCCRT plus ICIs is efficacious and safe for the management of LACC. The addition of ICIs to CCRT improved the rates of PFS and OS in patients with LACC. The adverse effects of immunotherapy-related AEs should be strictly examined and managed in a timely manner.

Predictive value of bowel dose-volume for severe radiation-induced lymphopenia and survival in cervical cancer

BackgroundRadiation-induced lymphopenia (RIL) is closely related to the prognosis of cervical cancer patients and may affect the efficacy of immune checkpoint inhibitors (ICIs). However, the factors influencing RIL are not very clear. In addition to bone marrow (BM) dose-volume, animal studies indicate radiation-induced bowel injury may be a more crucial factor. Further clarification of the correlation between RIL and bowel dose-volume is important for cervical cancer treatment.MethodsCervical cancer patients treated with postoperative radiotherapy or radical radiotherapy were eligible for this retrospective study. Clinical characteristics, dose parameters of bowel and BM, planning target volume (PTV) size, overall survival (OS) and progression-free survival (PFS) were recorded. The absolute lymphocyte count<0.5×109/L at radiotherapy end was defined as severe RIL (sRIL). Hazard ratio (HR) and 95% confidence interval (Cl)were estimated using Cox regression models. Survival curve was plotted using the Kaplan-Meier method. On this basis, the receiver operating characteristics (ROC) curve was used to calculate the area under the curve (AUC) for radiation parameters with sRIL as the state variable.ResultA total of 118 cervical cancer patients were included in this study, with a median follow-up time of 57.6 months. In multivariable Cox regression analysis, international Federation of Gynecology and obstetrics (FIGO) stage (HR, 11.806; 95% CI, 3.256-42.809; p<0.001), concurrent chemotherapy (HR, 0.200; 95% CI, 0.054-0.748; p=0.017), sRIL after radiotherapy (HR, 6.009; 95% CI, 1.361-26.539; p=0.018), and pathological type (HR, 2.261; 95% CI, 1.043-4.901; p=0.039) were significantly correlated with OS. Patients with sRIL had significantly decreased OS (79.1% vs 94.1%; HR, 3.81; 95%CI, 1.46-9.92; p=0.023). In binary logistic regression analysis, sRIL was significantly correlated with bowel V45 (Odds radio (OR), 1.025; 95%CI, 1.007-1.044; p=0.007), BM V10 (OR, 0.987; 95%CI, 0.978-0.997; p=0.011), BM V20 (OR, 1.017; 95%CI, 1.002-1.031, p=0.027), and PTV size (OR, 0.998; 95%CI, 0.996-1.000; p=0.026). The ROC curve showed, bowel V45 (AUC=0.787, p<0.001) was the best indicator for predicting sRIL.ConclusionSRIL after radiotherapy could significantly predict decreased OS. In addition, sRIL is associated with higher bowel, BM dose-volume, PTV size, indicating that the bowel may be an important organ leading to an increased risk of sRIL.

Case report: Complete response in TMB-H advanced uterine clear cell carcinoma: a case analysis of paclitaxel albumin-bound combined with PD-1/CTLA-4 bispecific antibody

BackgroundUterine clear cell carcinoma (UCCC) is a rare and aggressive subtype of endometrial cancer, often presenting at an advanced stage with poor prognosis. Treatment options for advanced or recurrent UCCC are currently limited, especially after platinum-based chemotherapy has failed.Case presentationWe present the case of a 49-year-old female diagnosed with stage IV uterine clear cell carcinoma. The patient had a history of atrial fibrillation and initially received several surgical interventions and platinum-based chemotherapy, but these treatments resulted in poor outcomes and rapid tumor progression. Genetic testing showed a high tumor mutation burden (TMB-H, 42.24 mutations/Mb) with stable microsatellites and a suspected harmful mutation in the PMS2 gene. After conventional therapies failed, the patient received a combination treatment of cadonilimab (375 mg) and albumin-bound paclitaxel (380 mg) for six cycles. This was followed by cadonilimab monotherapy for maintenance. This treatment regimen led to a complete response (CR), with no detectable abdominal fluid or enlarged lymph nodes by January 4, 2023. The CR status was maintained during a follow-up on April 07, 2024. The adverse effects included severe myelosuppression, mild skin reactions, hypothyroidism, and Grade 3 hyperglycemia, all of which were managed symptomatically.ConclusionThis case illustrates how effective AK104/Cadonilimab (a PD-1/CTLA-4 bispecific) can be when combined with albumin-bound paclitaxel for treating advanced UCCC, especially in patients who have not responded to standard therapies. The patient’s complete and lasting response shows the potential of PD-1/CTLA-4 bispecific immunotherapy. This suggests that cadonilimab could provide important clinical benefits for patients with advanced or recurrent UCCC.

Prognostic role of different PD-L1 expression patterns and tumor-infiltrating lymphocytes in high-grade serous ovarian cancer: a systematic review and meta-analysis

BackgroundThe prognostic value of programmed cell death ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in high-grade serous ovarian cancer (HGSOC) remains a controversial topic in the research field. To comprehensively assess the importance of PD-L1 and TILs in this particular subtype of ovarian cancer, we performed a meta-analysis.MethodsWe conducted a comprehensive search of PubMed, Embase, Scopus, Web of Science, and Cochrane Library databases up to December 25, 2022. The association between PD-L1, TILs, and survival outcomes was evaluated using the combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs).ResultsThis meta-analysis comprised 11 trials involving a total of 1746 cases. The results revealed no significant association between PD-L1 expression in tumor cells (TCs) and overall survival (OS, HR = 0.76, 95% CI: 0.52-1.09, p = 0.136) or progression-free survival (PFS, HR = 0.71, 95% CI: 0.4 -1.24, p = 0.230). Nevertheless, a correlation was observed between PD-L1 expression in immune cells (ICs) and OS (HR = 0.73, 95% CI: 0.55-0.97, p = 0.031). Furthermore, the presence of CD8+ and PD-1+ TILs was found to significantly enhance OS (HR = 0.70, 95% CI = 0.55-0.87, p = 0.002; HR = 0.57, 95% CI = 0.40-0.80, p = 0.001, respectively) and PFS (HR = 0.62, 95% CI = 0.41-0.92, p = 0.019; HR = 0.52, 95% CI = 0.35-0.78, p = 0.002, respectively), whereas the presence of CD3+ and CD4+ TILs was positively associated with OS (HR = 0.50, 95% CI = 0.29-0.87, p = 0.014; HR = 0.55, 95% CI = 0.34-0.91, p = 0.020, respectively).ConclusionThis study indicates a positive correlation between ICs-derived PD-L1 and survival, while no significant correlation was observed between TCs-derived PD-L1 and prognosis. These results highlight the importance of studying PD-L1 expression in ICs as a prognostic predictor. In addition, the presence of TILs was found to significantly improve patient survival, suggesting that TILs may be a valuable prognostic biomarker.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022366411.

Second-line monotherapy with a PD-1/CTLA-4 inhibitor effectively treated multiple brain and lung metastases of cervical cancer: a case report

BackgroundBrain metastasis (BM) from cervical cancer (CC) is extremely rare. The prognosis of BM is poor. To our knowledge, no satisfactory therapeutic and standard effective treatments have been established. Immune checkpoint inhibitors (ICIs) treatment is emerging as a promising treatment in recurrence and metastasis(B/M) cervical cancer in recent years.CaseWe present a 50-year-old patient with CC who developed multiple metastasis (lung, brain and skin) 2 years after postoperative chemoradiotherapy. She received palliative therapy included chemotherapy, resection and stereotactic radiosurgery of BM with poor response. Then, the patient received second-line palliative monotherapy with a PD-1/CTLA-4 inhibitor(cadonilimab) and achieved clinical very good partial response (VGPR), a progression-free survival (PFS) of 14 months and overall survival of more than 18 months since BM.ConclusionWe report a case of cervical cancer with multiple metastasis receiving cadonilimab and achieved considerable response and survival benefit.

Case report: A case of sintilimab-induced recurrent diabetic ketoacidosis and thyroid dysfunction in a patient with advanced cervical carcinoma

Immune checkpoint inhibitors (ICIs) have radically altered cancer treatment, but immune toxicities called immune-related adverse events (irAEs), particularly endocrine toxicities, such as acute-onset diabetes and thyroid dysfunction, pose challenges. Although most irAEs have mild-to-moderate severity, failure to diagnose and treat them promptly can result in life-threatening complications. This report presents the case of a 50-year-old woman who developed ICI-induced diabetes mellitus (ICI-DM) during sintilimab treatment for advanced cervical carcinoma. The patient experienced repeated episodes of diabetic ketoacidosis (DKA) and subclinical hypothyroidism. Unlike the case of patients with typical type 1 diabetes mellitus (T1DM), our patient tested negative for β cell autoantibodies and progressed rapidly. Prompt recognition and insulin treatment are crucial for helping patients overcome such crises. Eventually, sintilimab was discontinued, and chemotherapy was initiated. This case report contributes to our understanding of ICI-DM. The significance of monitoring thyroid function and blood glucose levels before initiating ICI treatment to identify irAEs early and effectively manage them are important considerations.

(Nano)biotechnological approaches in the treatment of cervical cancer: integration of engineering and biology

Cervical cancer is one of the most malignant gynaecological tumors characterised with the aggressive behaviour of the tumor cells. In spite of the development of different strategies for the treatment of cervical cancer, the tumor cells have developed resistance to conventional therapeutics. On the other hand, nanoparticles have been recently applied for the treatment of human cancers through delivery of drugs and facilitate tumor suppression. The stimuli-sensitive nanostructures can improve the release of therapeutics at the tumor site. In the present review, the nanostructures for the treatment of cervical cancer are discussed. Nanostructures can deliver both chemotherapy drugs and natural compounds to increase anti-cancer activity and prevent drug resistance in cervical tumor. Moreover, the genetic tools such as siRNA can be delivered by nanoparticles to enhance their accumulation at tumor site. In order to enhance selectivity, the stimuli-responsive nanoparticles such as pH- and redox-responsive nanocarriers have been developed to suppress cervical tumor. Moreover, nanoparticles can induce photo-thermal and photodynamic therapy to accelerate cell death in cervical tumor. In addition, nanobiotechnology demonstrates tremendous potential in the treatment of cervical cancer, especially in the context of tumor immunotherapy. Overall, metal-, carbon-, lipid- and polymer-based nanostructures have been utilized in cervical cancer therapy. Finally, hydrogels have been developed as novel kinds of carriers to encapsulate therapeutics and improve anti-cancer activity.

Commentary: Immune cell infiltration and prognostic index in cervical cancer: insights from metabolism-related differential genes

Editorial: Community series in novel insights into immunotherapy targeting tumor microenvironment in ovarian cancer: volume II

Elucidating the role of tumor-associated ALOX5+ mast cells with transformative function in cervical cancer progression via single-cell RNA sequencing

BackgroundCervical cancer (CC) is the fourth most common malignancy among women globally and serves as the main cause of cancer-related deaths among women in developing countries. The early symptoms of CC are often not apparent, with diagnoses typically made at advanced stages, which lead to poor clinical prognoses. In recent years, numerous studies have shown that there is a close relationship between mast cells (MCs) and tumor development. However, research on the role MCs played in CC is still very limited at that time. Thus, the study conducted a single-cell multi-omics analysis on human CC cells, aiming to explore the mechanisms by which MCs interact with the tumor microenvironment in CC. The goal was to provide a scientific basis for the prevention, diagnosis, and treatment of CC, with the hope of improving patients’ prognoses and quality of life.MethodThe present study acquired single-cell RNA sequencing data from ten CC tumor samples in the ArrayExpress database. Slingshot and AUCcell were utilized to infer and assess the differentiation trajectory and cell plasticity of MCs subpopulations. Differential expression analysis of MCs subpopulations in CC was performed, employing Gene Ontology, gene set enrichment analysis, and gene set variation analysis. CellChat software package was applied to predict cell communication between MCs subpopulations and CC cells. Cellular functional experiments validated the functionality of TNFRSF12A in HeLa and Caski cell lines. Additionally, a risk scoring model was constructed to evaluate the differences in clinical features, prognosis, immune infiltration, immune checkpoint, and functional enrichment across various risk scores. Copy number variation levels were computed using inference of copy number variations.ResultThe obtained 93,524 high-quality cells were classified into ten cell types, including T_NK cells, endothelial cells, fibroblasts, smooth muscle cells, epithelial cells, B cells, plasma cells, MCs, neutrophils, and myeloid cells. Furthermore, a total of 1,392 MCs were subdivided into seven subpopulations: C0 CTSG+ MCs, C1 CALR+ MCs, C2 ALOX5+ MCs, C3 ANXA2+ MCs, C4 MGP+ MCs, C5 IL32+ MCs, and C6 ADGRL4+ MCs. Notably, the C2 subpopulation showed close associations with tumor-related MCs, with Slingshot results indicating that C2 subpopulation resided at the intermediate-to-late stage of differentiation, potentially representing a crucial transition point in the benign-to-malignant transformation of CC. CNVscore and bulk analysis results further confirmed the transforming state of the C2 subpopulation. CellChat analysis revealed TNFRSF12A as a key receptor involved in the actions of C2 ALOX5+ MCs. Moreover, in vitro experiments indicated that downregulating the TNFRSF12A gene may partially inhibit the development of CC. Additionally, a prognosis model and immune infiltration analysis based on the marker genes of the C2 subpopulation provided valuable guidance for patient prognosis and clinical intervention strategies.ConclusionsWe first identified the transformative tumor-associated MCs subpopulation C2 ALOX5+ MCs within CC, which was at a critical stage of tumor differentiation and impacted the progression of CC. In vitro experiments confirmed the inhibitory effect of knocking down the TNFRSF12A gene on the development of CC. The prognostic model constructed based on the C2 ALOX5+MCs subset demonstrated excellent predictive value. These findings offer a fresh perspective for clinical decision-making in CC.

Integrating chronic inflammation and hypoxia: the potential role of HIF-1α in tumor behavior and therapy response in high-grade serous ovarian cancer

High-grade serous ovarian carcinoma (HGSOC) is marked by late diagnosis and chemoresistance, partly driven by chronic inflammation and hypoxia in the tumor microenvironment. Hypoxia-inducible factor 1-alpha (HIF-1α) is a key regulator of these processes; however, its spatial distribution, interaction with inflammation, and effect on chemotherapy response in HGSOC remain unclear. This retrospective study included 28 advanced HGSOC patients treated with neoadjuvant chemotherapy (NACT). Samples were collected at primary surgery (PS) (ovarian and peritoneal tissue, plasma, ascites) and post-NACT at interval debulking surgery (IDS) (omentum, peritoneal tissue, plasma). HIF-1α mRNA expression varied by site, with higher levels in omental and peritoneal tissues compared to ovarian tissue. Plasma and ascites concentrations were significantly correlated, although the mean ascites concentration was lower. Elevated HIF-1α concentration in ascites and plasma at baseline correlated with ESR (erythrocyte sedimentation rate) >30 mm/h, which was also correlated with BRCA mutation status. No correlation was found between HIF-1α and CRP (C-reactive protein) levels. Higher HIF-1α concentrations in ascites and plasma were linked to poor chemotherapy response (CRS1) at IDS. No significant changes in plasma HIF-1α, ESR, or peritoneal HIF-1α mRNA expression were observed before and after chemotherapy. Increased peritoneal HIF-1α at baseline showed a trend toward shorter progression-free survival. These findings suggest that HIF-1α may reflect hypoxia-inflammation crosstalk associated with chemoresistance and progression in HGSOC. The hypoxic-inflammatory microenvironment appears to persist despite chemotherapy and could contribute to ongoing disease activity. However, these observations require validation in independent cohorts before any prognostic or predictive implications can be considered.

Case report: Characterization of the immunologic and molecular landscape in a unique presentation of invasive lobular carcinoma with concurrent uterine carcinosarcoma treated with immunotherapy

Invasive lobular breast cancer (ILC) is characterized by a relatively high risk for late recurrence and a unique metastatic pattern with an increased risk for metastasis to gynecologic organs and peritoneum. We present a unique case of recurrent ILC with metastasis to the abdominal peritoneum as well as the uterine myometrium and cervix. Treatment was complicated by the discovery of concomitant uterine carcinosarcoma. This patient was effectively treated with a combination of hormonal therapy for her metastatic ILC and a combination of chemotherapy and immunotherapy for uterine carcinosarcoma. Molecular evaluation revealed a characteristic CDH1 mutation within the ILC and a PI3KCA mutation within the uterine carcinosarcoma, both of which have been linked to epithelial-to-mesenchymal transitions. Examination of the tumor immune microenvironment revealed proportionally more cytotoxic NK cells. This robust immune infiltration may be an indicator of the response to immunotherapy observed in this tumor or a result of the metastatic breast cancer within the uterus. This report provides a characterization of the molecular and immunologic landscape in this case with metastatic ILC and uterine carcinosarcoma.

Detection of cytokines in cervicovaginal lavage in HIV-infected women and its association with high-risk human papillomavirus

BackgroundWomen living with HIV/AIDS (WLHA) have an increased prevalence of high-risk HPV infection (HR-HPV) and cervical intraepithelial neoplasia (CIN) and a greater risk of cervical cancer despite access to a new generation of antiretroviral therapy. The aim of this study is to evaluate the concentrations of different cytokines involved in the local immune response in WLHA, which is fundamental for understanding the pathogenesis of HPV-related cancer in this population.MethodsIL-1β, IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α, IP-10, GM-CSF, and MIP-1α were investigated in the cervicovaginal lavage (CVL) of 106 WLHA attending at Hospital Universitario Professor Edgard Santos in Salvador, Bahia, Brazil, during the period December 2019 to April 2023 by Luminex®. All participants were also tested for Chlamydia trachomatis and Neisseria gonorrhoeae and underwent colposcopy, Pap smear, and Nugent score. HIV plasma viral load (VL) and CD4 cell count were performed for all WLHA.ResultsIn this study, 22.6% (24/106) of WLHA were infected with HR-HPV. A higher proportion of patients with HR-HPV (66.7%) had detectable levels of IL-10 than those negative ones (40.2%, p = 0.02). More premenopausal women had either IL-6 (51.4%) or IP-10 (58.3%) than those in menopausal status (26.5% for IL-6 and 32.4% for IP-10, p = 0.013 and p = 0.011, respectively). Vaginosis was negatively associated with detection of IP-10 (24.2% vs. 61.4%, p < 0.001) and INF-γ (39.4% vs. 68.6%, p = 0.005). A positive association was detected for IL-1β (66.7 vs. 37.1%, p = 0.005) and IL-10 (63.6% vs. 37.1%, p = 0.01). VL and CD4 were not associated with the studied cytokines.ConclusionWe demonstrated a positive association between IL-10 and HPV infection in CVL, suggesting the predominance of the Th2 response in HIV/HPV co-infected patients. However, further studies with longer follow-up will be needed to evaluate the association of IL-10 with HPV infection, CIN, and cervical cancer in WLHA.

The complement regulatory protein CD46 serves as a novel biomarker for cervical cancer diagnosis and prognosis evaluation

BackgroundCD46 has been revealed to be a key factor in malignant transformation and cancer treatment. However, the clinical significance of CD46 in cervical cancer remains unclear, and this study aimed to evaluate its role in cervical cancer diagnosis and prognosis evaluation.MethodsA total of 180 patients with an initial diagnosis of cervical cancer were enrolled at Taizhou Hospital of Zhejiang Province, China. The plasma levels of soluble CD46 (sCD46) and the expression of membrane-bound CD46 (mCD46) were detected by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC), respectively.ResultsCD46 was found to be significantly upregulated in cervical cancer tissues vs. normal tissues, while no CD46 staining was detected in paired adjacent noncancerous tissues. CD46 staining was more pronounced in cancer cells than in stromal cells in situ (in tissues). Moreover, the plasma levels of sCD46 were able to some extent discriminate between cancer patients and healthy women (AUC=0.6847, 95% CI:0.6152–0.7541). Analysis of Kaplan–Meier survival curves revealed that patients with low CD46 expression had slightly longer overall survival (OS) than patients with high CD46 expression in the tumor microenvironment, but no significant difference. Univariate Cox regression analysis revealed that CD46 (P=0.034) is an independent risk factor for OS in cervical cancer patients.ConclusionThe present study demonstrated that cervical cancer patients exhibit aberrant expression of CD46, which is closely associated with a poor prognosis, suggesting that CD46 plays a key role in promoting cervical carcinogenesis and that CD46 could serve as a promising potential target for precision therapy for cervical cancer.

The relationship between polycystic ovary syndrome and gynecological cancers: neurotransmitter metabolism changes and immune regulation

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting approximately 10% of middle-aged women worldwide. It is characterized by hirsutism, anovulation, and polycystic ovaries. Various factors, including environmental toxins, inflammation, oxidative stress, and insulin resistance, contribute to the progression of this condition. PCOS is also associated with metabolic disturbances, such as abnormal hormone and neurotransmitter metabolism, leading to obesity, hyperandrogenemia, and type 2 diabetes. Among female cancers, breast cancer, endometrial cancer, and ovarian cancer have high incidence rates and pose significant threats to women’s health. Studies suggest a potential link between PCOS and these gynecological cancers. Consequently, hormonal alterations in PCOS patients may influence tumorigenesis and metastasis. Moreover, PCOS is characterized by chronic low-grade inflammation, including dysregulated pro-inflammatory cytokine secretion, increased immune cell proliferation, and endothelial dysfunction. These factors contribute to cancer development, primarily through impaired immune metabolism, preventing effective tumor cell clearance and facilitating metastasis. This review synthesizes current knowledge on the mechanistic links between PCOS and gynecological cancers, focusing on the roles of immune cell dysfunction, aberrant cytokine secretion, and neurotransmitter metabolism. Therapeutic strategies, including hormonal interventions, insulin sensitizers, and lifestyle modifications, may mitigate cancer risk by modulating these pathways. This review highlights critical gaps in understanding PCOS-related oncogenesis and advocates for further research to elucidate molecular mechanisms and optimize clinical management.

Immune cell infiltration and prognostic index in cervical cancer: insights from metabolism-related differential genes

BackgroundCervical cancer remains a significant gynecologic malignancy in both China and the United States, posing a substantial threat to women’s lives and health due to its high morbidity and mortality rates. Altered energy metabolism and dysregulated mitochondrial function play crucial roles in the development, growth, metastasis, and recurrence of malignant tumors. In this study, we aimed to predict prognosis and assess efficacy of anti-tumor therapy in cervical cancer patients based on differential genes associated with mitochondrial metabolism.MethodsTranscriptomic data and clinical profiles of cervical cancer patients were retrieved from the TCGA and GEO databases. Differential gene-related cellular pathways were identified through GO, KEGG, and GSEA analyses. Prognostic indices were constructed using LASSO regression analysis. Immune cell infiltration was assessed using CIBERSORT and ssGSEA, and the correlation between immune checkpoint inhibitor genes and differential genes was examined. Tumor mutation load (TMB) and its association with prognostic indices were analyzed using nucleotide variant data from the TCGA database. Patient response to immunotherapy and sensitivity to antitumor drugs were determined using the TIDE algorithm and the oncoPredic algorithm, respectively.ResultsA prognostic index based on metabolism-related differential genes was developed to predict the clinical outcome of cervical cancer patients, enabling their classification into two distinct subtypes. The prognostic index emerged as an independent risk factor for unfavorable prognosis. The high-index group exhibited a significantly worse overall prognosis, along with elevated tumor mutation burden (TMB), increased immune cell infiltration, and lower TIDE scores, indicating a potential benefit from immunotherapy. Conversely, the low-index group demonstrated increased sensitivity to metabolism-related antitumor agents, specifically multikinase inhibitors.ConclusionThe aim of this study was to develop a prognostic index based on differential genes associated with mitochondrial metabolism, which could be used to predict cervical cancer patients’ prognoses. When combined with TIDE and TMB analyses, this prognostic index offers insights into the immune cell infiltration landscape, as well as the potential efficacy of immunotherapy and targeted therapy. Our analysis suggests that the Iron-Sulfur Cluster Assembly Enzyme (ISCU) gene holds promise as a biomarker for cervical cancer immunotherapy.

Targeted proteomics-determined multi-biomarker profiles developed classifier for prognosis and immunotherapy responses of advanced cervical cancer

Background Cervical cancer (CC) poses a global health challenge, with a particularly poor prognosis in cases of recurrence, metastasis, or advanced stages. A single biomarker is inadequate to predict CC prognosis or identify CC patients likely to benefit from immunotherapy, presumably owing to tumor complexity and heterogeneity. Methods Using advanced Olink proteomics, we analyzed 92 oncology-related proteins in plasma from CC patients receiving immunotherapy, based upon the comparison of protein expression levels of pre-therapy with those of therapy-Cycle 6 in the partial response (PR) group and progressive disease (PD) group, respectively. Results 55 proteins were identified to exhibit differential expression trends across pre-therapy and post-therapy in both PR and PD groups. Enriched GO terms and KEGG pathways were associated with vital oncological and immunological processes. A logistic regression model, using 5 proteins (ITGB5, TGF-α, TLR3, WIF-1, and ERBB3) with highest AUC values, demonstrated good predictive performance for prognosis of CC patients undergoing immunotherapy and showed potential across different cancer types. The effectiveness of these proteins in prognosis prediction was further validated using TCGA-CESC datasets. A negative correlation and previously unidentified roles of WIF-1 in CC immunotherapy was also first determined. Conclusion Our findings reveal multi-biomarker profiles effectively predicting CC prognosis and identifying patients benefitting most from immunotherapy, especially for those with limited treatment options and traditionally poor prognosis, paving the way for personalized immunotherapeutic treatments and improved clinical strategies.

Tumor immune microenvironment changes are associated with response to neoadjuvant chemotherapy and long-term survival benefits in advanced epithelial ovarian cancer: A pilot study

Little is known about the association between efficacy of neoadjuvant chemotherapy (NACT)/survival and the dynamic change of tumor immune environment (TIME) during treatment in epithelial ovarian cancer (EOC). This study investigated the TIME landscape of treatment-naive EOC tumors using multiplex immunofluorescence and associated the TIME before and after platinum-based NACT with treatment efficacy and prognosis in 33 patients with advanced EOC. NACT significantly increased the density of CD8+ T cells (P = 0.033), CD20+ B cells (P = 0.023), CD56 NK cells (P = 0.041), PD-1+ cells (P = 0.042), and PD-L1+CD68+ macrophages (P = 0.005) in the tissue specimens. Response to NACT was evaluated using CA125 response and chemotherapy response score (CRS). Compared with the non-responders, the responders displayed a larger proportion of tumors showing increase in the infiltration of CD20+ cells (P = 0.046) and in the M1/M2 ratio (P = 0.038) as well as fewer tumors showing increase in the infiltration of CD56bright cells (P = 0.041). No association was found between pre-NACT TIME and response to NACT. Density of pre-NACT CD8+ cells was positively associated with longer progression-free survival (PFS) (P = 0.011) and overall survival (OS) (P = 0.048). Post-NACT CD20+ and CD163+ macrophages (M2) infiltrates were associated with prolonged (P = 0.005) and shortened PFS (P = 0.021), respectively. Increase in the density of CD4+ T cells was predictive for longer PFS (P = 0.022) and OS (P = 0.023). In the multivariate analysis, high density of CD8+ cells pre-NACT (P = 0.042) were independently associated with improved OS.

Efficacy and safety of BVAC-C in HPV type 16- or 18–positive cervical carcinoma who failed 1st platinum-based chemotherapy: a phase I/IIa study

BackgroundBVAC-C, a B cell– and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, was well tolerated in HPV–positive recurrent cervical carcinoma patients in a phase I study. This phase IIa study investigates the antitumor activity of BVAC-C in patients with HPV 16– or 18–positive cervical cancer who had experienced recurrence after a platinum-based combination chemotherapy.Patients and methodsPatients were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks; Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks; Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks with topotecan at 2, 6, 10, 14 weeks. Primary endpoints were safety and objective response rate (ORR) as assessed by an independent radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included the disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).ResultsOf the 30 patients available for analysis, the ORR was 19.2% (Arm 1: 20.0% (3/15), Arm 2: 33.3% (2/6), Arm3: 0%) and the DCR was 53.8% (Arm 1: 57.1%, Arm 2: 28.6%, Arm3: 14.3%). The median DOR was 7.5 months (95% CI 7.1–not reported), the median PFS was 5.8 months (95% CI 4.2–10.3), and the median OS was 17.7 months (95% CI 12.0–not reported). All evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α) but also potent E6/E7-specific T cell responses upon vaccinations. Immune responses of patients after vaccination were correlated with their clinical responses.ConclusionBVAC-C represents a promising treatment option and a manageable safety profile in the second-line setting for this patient population. Further studies are needed to identify potential biomarkers of response.Clinical trial registrationClinicalTrials.gov, identifier NCT02866006.

The preoperative platelet to neutrophil ratio and lymphocyte to monocyte ratio are superior prognostic indicators compared with other inflammatory biomarkers in ovarian cancer

BackgroundPrevious studies have suggested that the ratios of immune-inflammatory cells could serve as prognostic indicators in ovarian cancer. However, which of these is the superior prognostic indicator in ovarian cancer remains unknown. In addition, studies on the prognostic value of the platelet to neutrophil ratio (PNR) in ovarian cancer are still limited.MethodsA cohort of 991 ovarian cancer patients was analyzed in the present study. Receiver operator characteristic (ROC) curves were utilized to choose the optimal cut-off values of inflammatory biomarkers such as neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and PNR. The correlation of inflammatory biomarkers with overall survival (OS) and relapse-free survival (RFS) was investigated by Kaplan-Meier methods and log-rank test, followed by Cox regression analyses.ResultsKaplan-Meier curves suggested that LMR<3.39, PLR≥181.46, and PNR≥49.20 had obvious associations with worse RFS (P<0.001, P=0.018, P<0.001). Multivariate analysis suggested that LMR (≥3.39 vs. <3.39) (P=0.042, HR=0.810, 95% CI=0.661-0.992) and PNR (≥49.20 vs. <49.20) (P=0.004, HR=1.351, 95% CI=1.103-1.656) were independent prognostic indicators of poor RFS. In addition, Kaplan-Meier curves indicated that PLR≥182.23 was significantly correlated with worse OS (P=0.039).ConclusionTaken together, PNR and LMR are superior prognostic indicators compared with NLR, PLR, and SII in patients with ovarian cancer.

STING agonist inflames the cervical cancer immune microenvironment and overcomes anti-PD-1 therapy resistance

BackgroundCervical cancer poses a significant global threat to women’s health. However, current therapeutic interventions, such as radiotherapy, chemotherapy, surgical resection, and immune checkpoint inhibitors, face limitations in the advanced stages of the disease. Given the immunosuppressive microenvironment in cervical cancer, it is imperative to explore novel perspectives. In this regard, STING agonists have emerged as promising candidates.MethodsThe expression profiles and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Prognostic analysis of STING downstream genes (CCL5, CXCL9, CXCL10) and immune infiltration analysis were conducted using Kaplan-Meier Plotter, ESTIMATE, and deconvo_CIBERSOR. Single-cell RNA-seq (scRNA-seq) analysis was conducted to evaluate the potential of MSA-2 in cervical cancer treatment employing SingleR, chi-squared test, and Gene Set Enrichment Analysis (GSEA). Cellular interaction analysis utilized the CellChat package to assess the potentiation of cellular interaction following MSA-2 administration. Murine tumor models involving U14 and TC-1, were conducted, and the IF of tissue was subsequently conducted to assess the tumor microenvironment status after treatment.ResultsPrognosis in cervical cancer correlated with elevated expression of STING downstream genes, indicating prolonged survival and reduced recurrence. These genes positively correlated with immune infiltration, influencing stromal scores, immune scores, and estimate scores. Specific immune cell populations, including CD8+ T cells, M1-type macrophages, NK cells, and T follicular helper cells, were associated with STING downstream genes. scRNA-seq in a classic immune-excluded model revealed that MSA-2 exerts priming and activating functions on vital components within TME, and intensifies their intercellular communications. The in vivo assay ultimately demonstrated that MSA-2, either as a standalone treatment or in combination with anti-PD-1, effectively suppressed the growth of subcutaneous cervical tumors. Moreover, the combination strategy significantly augmented efficacy compared to anti-PD-1 monotherapy by eliciting a robust antitumor immune response.ConclusionThis study highlights the pivotal role of the STING pathway and the potential of MSA-2 in reshaping the immune microenvironment in cervical cancer. Combining MSA-2 with immune checkpoint inhibitors presents a transformative approach, holding promise for improved prognosis. Further investigations are warranted to explore the broader immune landscape and potential long-term effects of MSA-2 in cervical cancer treatment.

Decoding the tumor microenvironment and molecular mechanism: unraveling cervical cancer subpopulations and prognostic signatures through scRNA-Seq and bulk RNA-seq analyses

BackgroundCervical carcinoma (CC) represents a prevalent gynecological neoplasm, with a discernible rise in prevalence among younger cohorts observed in recent years. Nonetheless, the intrinsic cellular heterogeneity of CC remains inadequately investigated.MethodsWe utilized single-cell RNA sequencing (scRNA-seq) transcriptomic analysis to scrutinize the tumor epithelial cells derived from four specimens of cervical carcinoma (CC) patients. This method enabled the identification of pivotal subpopulations of tumor epithelial cells and elucidation of their contributions to CC progression. Subsequently, we assessed the influence of associated molecules in bulk RNA sequencing (Bulk RNA-seq) cohorts and performed cellular experiments for validation purposes.ResultsThrough our analysis, we have discerned C3 PLP2+ Tumor Epithelial Progenitor Cells as a noteworthy subpopulation in cervical carcinoma (CC), exerting a pivotal influence on the differentiation and progression of CC. We have established an independent prognostic indicator—the PLP2+ Tumor EPCs score. By stratifying patients into high and low score groups based on the median score, we have observed that the high-score group exhibits diminished survival rates compared to the low-score group. The correlations observed between these groups and immune infiltration, enriched pathways, single-nucleotide polymorphisms (SNPs), drug sensitivity, among other factors, further underscore their impact on CC prognosis. Cellular experiments have validated the significant impact of ATF6 on the proliferation and migration of CC cell lines.ConclusionThis study enriches our comprehension of the determinants shaping the progression of CC, elevates cognizance of the tumor microenvironment in CC, and offers valuable insights for prospective CC therapies. These discoveries contribute to the refinement of CC diagnostics and the formulation of optimal therapeutic approaches.

The biological roles of CD24 in ovarian cancer: old story, but new tales

CD24 is a glycosylphosphatidylinositol linked molecular which expressed in diverse malignant tumor cells, particular in ovarian carcinoma cells and ovarian carcinoma stem cells. The CD24 expression is associated with increased metastatic potential and poor prognosis of malignancies. CD24 on the surface of tumor cells could interact with Siglec-10 on the surface of immune cells, to mediate the immune escape of tumor cells. Nowadays, CD24 has been identified as a promising focus for targeting therapy of ovarian cancer. However, the roles of CD24 in tumorigenesis, metastasis, and immune escape are still not clearly demonstrated systematically. In this review, we i) summarized the existing studies on CD24 in diverse cancers including ovarian cancer, ii) illustrated the role of CD24-siglec10 signaling pathway in immune escape, iii) reviewed the existing immunotherapeutic strategies (targeting the CD24 to restore the phagocytic effect of Siglec-10 expressing immune cells) based on the above mechanisms and evaluated the priorities in the future research. These results might provide support for guiding the CD24 immunotherapy as the intervention upon solid tumors.

Clinical benefit analysis of PD-1 inhibitors in patients with advanced, recurrent or metastatic cervical cancer: a meta-analysis and systematic review

PurposeThis study aims to comprehensively evaluate the efficacy and safety of programmed cell death protein-1 (PD-1) in patients with advanced, recurrent, or metastatic cervical cancer (ARMCC) and identify the population that may benefit the most.MethodsWe conducted a search of PubMed, EMBASE, and the Cochrane Collaboration Library from their inception to September 2023. We extracted and analyzed the results related to the efficacy and safety of PD-1 in patients with ARMCC. The primary endpoints included the overall objective response rate (ORR) and adverse events (AEs), while the secondary endpoints encompassed the 1-year overall survival (OS) rate, 1-year progression-free survival (PFS) rate, as well as OS and PFS. We used a random effects model to conduct a meta-analysis on single-group rates, and the Mantel-Haenszel method was utilized to compare the ORR and the incidence of AEs.ResultsOur study included a total of 21 trials involving 2,097 patients. The ORR of the combination of PD-1 inhibitors with chemotherapy was 56.36%, the combination of PD-1 inhibitors with anti-angiogenic agents was 38.72%, the combination of PD-1 inhibitors with Cytotoxic T-lymphocyte antigen 4 inhibitors was 25.60%, and PD-1 inhibitor monotherapy was 15.99%. The subgroup analysis showed that the group of patients with squamous cell carcinoma (SCC) exhibited a significantly higher ORR compared to the non-SCC group in patients who received PD-1 inhibitors combined with other anti-tumor drugs (Odds Ratio =2.43, P=0.002). Additionally, the group of patients with a programmed death-ligand 1 combined positive score (PD-L1 CPS) ≥1 exhibited a significantly higher ORR compared to the PD-L1 CPS <1 group in patients who received PD-1 inhibitor monotherapy (OR=4.14, P=0.02). PD-1 inhibitor monotherapy or PD-1 inhibitors combined with chemotherapy did not significantly increase the incidence of all grades of adverse events (Relative Risk=0.99, p=0.788) or the incidence of serious adverse events (RR=0.99, p=0.788) compared to chemotherapy alone.ConclusionPD-1 inhibitors demonstrate outstanding efficacy in the treatment of patients with ARMCC. Patients with SCC may benefit more from treatments including PD-1 inhibitors in combination with other anti-tumor drugs, and PD-L1 CPS ≥1 can be considered a favorable indicator of immune therapy response. Importantly, the use of PD-1 inhibitor monotherapy or PD-1 inhibitors in combination with chemotherapy did not lead to an increased incidence of AEs compared with chemotherapy alone, indicting safety during treatment.Systematic Review RegistrationPROSPERO (CRD42023457945).

Acute retinal necrosis in a patient with cervical malignant tumor treated with sintilimab: a case report and literature review

Acute retinal necrosis (ARN) is an inflammatory disease that is primarily caused by herpesvirus infection, most commonly varicella-zoster virus (VZV), followed by herpes simplex virus (HSV) and occasionally cytomegalovirus (CMV). Sintilimab is an immune checkpoint inhibitor (ICI) that can enhance the body’s anti-tumor immune response. However, treatment with ICIs may lead to reactivation of the VZV. Here, we present a case of ARN caused by VZV infection in a patient receiving sintilimab for cervical cancer. A 64-year-old female patient developed vision loss and floaters with left eye redness for one week after 22 cycles of sintilimab for cervical cancer. Based on clinical manifestations, ophthalmological examination, and vitreous humor biopsy, the patient was diagnosed with acute retinal necrosis syndrome secondary to VZV. After receiving systemic antiviral and anti-inflammatory therapy, retinal necrosis lesions and visual function improved. In conclusion, clinicians should be aware of the risk of ARN when using sintilimab and should actively monitor patients for prompt diagnosis and optimal management of this rare adverse drug reaction.

Case report: Giant lymph node metastases: a new opportunity for cancer radioimmunotherapy?

BackgroundDespite the significant progress made in radiotherapy and chemotherapy for the treatment of cervical cancer, patients with lymph node metastasis still have a poor prognosis. It is widely accepted that lymph node metastasis plays a crucial role in the spread of cancer to other organs and is considered an independent factor in predicting a poor prognosis. However, recent research suggests that the importance of lymph nodes in tumor therapy needs to be reevaluated, as preserving the integrity of lymph nodes before immunotherapy can enhance treatment effectiveness.Case presentationIn this report, we present two cases of advanced cervical cancer patients with giant metastatic lymph node lesions in the neck. These patients were effectively treated with a combination of local radiotherapy and immunotherapy after conventional chemoradiotherapy had failed. The combination therapy resulted in significant clinical improvements, with patient 1 achieving over 12 months of progression-free survival (PFS) and patient 2 maintaining sustained remission for an impressive 24 months.ConclusionsThe combination of local radiotherapy and immunotherapy shows promise as a viable treatment option for cervical cancer patients with distant lymph node metastasis, and the giant lymph node metastases may play an important role in this process, which might provide a new opportunity for cancer radioimmunotherapy.

Intraperitoneal metastasis of ovarian cancer: new insights on resident macrophages in the peritoneal cavity

Ovarian cancer metastasis occurs primarily in the peritoneal cavity. Orchestration of cancer cells with various cell types, particularly macrophages, in the peritoneal cavity creates a metastasis-favorable environment. In the past decade, macrophage heterogeneities in different organs as well as their diverse roles in tumor settings have been an emerging field. This review highlights the unique microenvironment of the peritoneal cavity, consisting of the peritoneal fluid, peritoneum, and omentum, as well as their own resident macrophage populations. Contributions of resident macrophages in ovarian cancer metastasis are summarized; potential therapeutic strategies by targeting such cells are discussed. A better understanding of the immunological microenvironment in the peritoneal cavity will provide a stepping-stone to new strategies for developing macrophage-based therapies and is a key step toward the unattainable eradication of intraperitoneal metastasis of ovarian cancer.

Comparative cost-effectiveness of first-line pembrolizumab plus chemotherapy vs. chemotherapy alone in persistent, recurrent, or metastatic cervical cancer

BackgroundTreating persistent, recurrent, or metastatic cervical cancer remains challenging. Although pembrolizumab, combined with chemotherapy and bevacizumab, offers a promising first-line option, its cost-effectiveness within the Chinese healthcare system has not been established.MethodsA partitioned survival model was constructed using patient data from the KEYNOTE-826 trial. Efficacy, safety, and economic data from both trial and real-world practices were utilized to determine the costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) of the treatment strategies. Comprehensive insights were gained through the sensitivity and subgroup analyses.ResultsOver five years, the combination of pembrolizumab, chemotherapy, and bevacizumab offered an additional 1.18 QALYs compared to that provided by standard treatments. This regimen increased the costs by US$ 134,502.57, resulting in an ICER of US$ 114,275.67 per QALY, relative to traditional treatment costs. The ICER for the pembrolizumab regimen was further calibrated to be US$ 52,765.69 per QALY. Both ICER values surpassed China’s established willingness-to-pay threshold. Importantly, subgroup analysis revealed enhanced cost-effectiveness in patients presenting with a programmed death-ligand 1 combined positive score (PD-L1 CPS) ≥10.ConclusionIntroducing pembrolizumab alongside chemotherapy and bevacizumab may not be a cost-effective primary strategy for advanced cervical cancer against current standards. However, for patients with a PD-L1 CPS ≥10, the therapeutic and economic outcomes could be improved by adjusting the pembrolizumab price.

Machine learning-based integration develops an immune-related risk model for predicting prognosis of high-grade serous ovarian cancer and providing therapeutic strategies

BackgroundHigh-grade serous ovarian cancer (HGSOC) is a highly lethal gynecological cancer that requires accurate prognostic models and personalized treatment strategies. The tumor microenvironment (TME) is crucial for disease progression and treatment. Machine learning-based integration is a powerful tool for identifying predictive biomarkers and developing prognostic models. Hence, an immune-related risk model developed using machine learning-based integration could improve prognostic prediction and guide personalized treatment for HGSOC.MethodsDuring the bioinformatic study in HGSOC, we performed (i) consensus clustering to identify immune subtypes based on signatures of immune and stromal cells, (ii) differentially expressed genes and univariate Cox regression analysis to derive TME- and prognosis-related genes, (iii) machine learning-based procedures constructed by ten independent machine learning algorithms to screen and construct a TME-related risk score (TMErisk), and (iv) evaluation of the effect of TMErisk on the deconstruction of TME, indication of genomic instability, and guidance of immunotherapy and chemotherapy.ResultsWe identified two different immune microenvironment phenotypes and a robust and clinically practicable prognostic scoring system. TMErisk demonstrated superior performance over most clinical features and other published signatures in predicting HGSOC prognosis across cohorts. The low TMErisk group with a notably favorable prognosis was characterized by BRCA1 mutation, activation of immunity, and a better immune response. Conversely, the high TMErisk group was significantly associated with C-X-C motif chemokine ligands deletion and carcinogenic activation pathways. Additionally, low TMErisk group patients were more responsive to eleven candidate agents.ConclusionOur study developed a novel immune-related risk model that predicts the prognosis of ovarian cancer patients using machine learning-based integration. Additionally, the study not only depicts the diversity of cell components in the TME of HGSOC but also guides the development of potential therapeutic techniques for addressing tumor immunosuppression and enhancing the response to cancer therapy.

A case report of small cell neuroendocrine carcinoma of the ovary and review of the literature

Small cell neuroendocrine carcinoma of the ovary is rare pathological type with an undefined mechanism, low incidence, but high metastatic rate, high aggressiveness, and very poor prognosis, and there are no standardized treatment protocols or guidelines. In this article, we report a 48-year-old woman diagnosed with small cell neuroendocrine carcinoma of the ovary after puncture biopsy of a pelvic mass, who underwent 8 cycles of paclitaxel+carboplatin regimen chemotherapy (with the addition of the anti-angiogenesis targeted agent bevacizumab in the first 2 times, and the immunosuppressant tirilizumab in the last 2 times), followed by 12 times of tirilizumab monotherapy maintenance therapy, which was highly effective. It is believed that with newer technologies, the use of surgery, chemotherapy combined with immunotherapy, targeted therapy, genetic testing and construction of animal tumor models will play a key role in the treatment and monitoring of the prognosis of this rare disease.

Editorial: Community series in novel insights into immunotherapy targeting tumor microenvironment in ovarian cancer: volume I

CD4+ conventional T cells-related genes signature is a prognostic indicator for ovarian cancer

IntroductionIt is believed that ovarian cancer (OC) is the most deadly form of gynecological cancer despite its infrequent occurrence, which makes it one of the most salient public health concerns. Clinical and preclinical studies have revealed that intratumoral CD4+ T cells possess cytotoxic capabilities and were capable of directly killing cancer cells. This study aimed to identify the CD4+ conventional T cells-related genes (CD4TGs) with respect to the prognosis in OC.MethodsWe obtained the transcriptome and clinical data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. CD4TGs were first identified from single-cell datasets, then univariate Cox regression was used to screen prognosis-related genes, LASSO was conducted to remove genes with coefficient zero, and multivariate Cox regression was used to calculate riskscore and to construct the CD4TGs risk signature. Kaplan-Meier analysis, univariate Cox regression, multivariate Cox regression, time-dependent receiver operating characteristics (ROC), decision curve analysis (DCA), nomogram, and calibration were made to verify and evaluate the risk signature. Gene set enrichment analyses (GSEA) in risk groups were conducted to explore the tightly correlated pathways with the risk group. The role of riskscore has been further explored in the tumor microenvironment (TME), immunotherapy, and chemotherapy. A risk signature with 11 CD4TGs in OC was finally established in the TCGA database and furtherly validated in several GEO cohorts.ResultsHigh riskscore was significantly associated with a poorer prognosis and proven to be an independent prognostic biomarker by multivariate Cox regression. The 1-, 3-, and 5-year ROC values, DCA curve, nomogram, and calibration results confirmed the excellent prediction power of this model. Compared with the reported risk models, our model showed better performance. The patients were grouped into high-risk and low-risk subgroups according to the riskscore by the median value. The low-risk group patients tended to exhibit a higher immune infiltration, immune-related gene expression and were more sensitive to immunotherapy and chemotherapy.DiscussionCollectively, our findings of the prognostic value of CD4TGs in prognosis and immune response, provided valuable insights into the molecular mechanisms and clinical management of OC.

The prognostic significance of human ovarian aging-related signature in breast cancer after surgery: A multicohort study

BackgroundRecent studies have shown that ovarian aging is strongly associated with the risk of breast cancer, however, its prognostic impact on breast cancer is not yet fully understood. In this study, we performed a multicohort genetic analysis to explore its prognostic value and biological features in breast cancer.MethodsThe gene expression and clinicopathological data of 3366 patients from the The Cancer Genome Atlas (TCGA) cohort, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort and the GSE86166 cohort were analyzed. A total of 290 ovarian aging-related genes (OARGs) were included in the establishment of the prognostic model. Furthermore, functional mechanisms analysis, drug sensitivity, and immune cell infiltration were investigated using bioinformatic methods.ResultsAn eight OARG-based signature was established and validated using independent cohorts. Two risk subgroups of patients with distinct survival outcomes were identified by the OARG-based signature. A nomogram with good predictive performance was developed by integrating the OARG risk score with clinicopathological factors. Moreover, the OARG-based signature was correlated with DNA damage repair, immune cell signaling pathways, and immunomodulatory functions. The patients in the low-risk subgroup were found to be sensitive to traditional chemotherapeutic, endocrine, and targeted agents (doxorubicin, tamoxifen, lapatinib, etc.) and some novel targeted drugs (sunitinib, pazopanib, etc.). Moreover, patients in the low-risk subgroup may be more susceptible to immune escape and therefore respond less effectively to immunotherapy.ConclusionsIn this study, we proposed a comprehensive analytical method for breast cancer assessment based on OARG expression patterns, which could precisely predict clinical outcomes and drug sensitivity of breast cancer patients.

GPR30-mediated non-classic estrogen pathway in mast cells participates in endometriosis pain via the production of FGF2

Pain is one of the main clinical symptoms of endometriosis, but its underlying mechanism is still not clear. Recent studies have shown that the secretory mediators of mast cells activated by estrogen are involved in the pathogenesis of endometriosis-related pain, but how estrogen-induced mast cell mediators are involved in endometriosis-related pain remains unclear. Here, mast cells were found to be increased in the ovarian endometriotic lesions of patients. They were also closely located closely to the nerve fibers in the ovarian endometriotic lesions from of patients with pain symptoms. Moreover, fibroblast growth factor 2 (FGF2)-positive mast cells were upregulated in endometriotic lesions. The concentration of FGF2 in ascites and the protein level of fibroblast growth factor receptor 1 (FGFR1) were higher in patients with endometriosis than in those without endometriosis, and they were correlated with pain symptoms. In vitro, estrogen could promote the secretion of FGF2 through G-protein-coupled estrogen receptor 30 (GPR30) via the MEK/ERK pathway in rodent mast cells. Estrogen-stimulated mast cells enhanced the concentration of FGF2 in endometriotic lesions and aggravated endometriosis-related pain in vivo. Targeted inhibition of the FGF2 receptor significantly restrained the neurite outgrowth and calcium influx in dorsal root ganglion (DRG) cells. Administration of FGFR1 inhibitor remarkably elevated the mechanical pain threshold (MPT) and prolonged the heat source latency (HSL) in a rat model of endometriosis. These results suggested that the up-regulated production of FGF2 by mast cells through non-classic estrogen receptor GPR30 plays a vital role in the pathogenesis of endometriosis-related pain.

NK cell-derived exosomes enhance the anti-tumor effects against ovarian cancer by delivering cisplatin and reactivating NK cell functions

Exosomes are membranous vesicles actively secreted by almost all cells and they deliver certain intracellular molecules, including nucleic acids, proteins, and lipids, to target cells. They are also considered to be good carriers for drug delivery due to their biocompatibility, high permeability, low immunogenicity, and low toxicity. Exosomes from immune cells were also reported to have immunomodulatory activities. Herein we evaluated the application of exosomes derived from expanded natural killer cells (eNK-EXO) for the treatment of ovarian cancer (OC). We demonstrate that eNK-EXO express typical protein markers of natural killer (NK) cells, can be preferentially uptaken by SKOV3 cells, and display cytotoxicity against OC cells. Furthermore, eNK-EXO loaded with cisplatin could sensitize drug-resistant OC cells to the anti-proliferation effect of cisplatin. In addition, we show that eNK-EXO could activate NK cells from immunosuppressive tumor microenvironment, the mechanism of which is explored by transcriptional analysis. In summary, eNK-EXO exhibit anti-tumor activity against OC on its own, could be used to deliver cisplatin and enhance its cytotoxic effect against drug-resistant OC cells and also reverse the immunosuppression of NK cells, which may lead to great prospect of using eNK-EXO in the treatment of OC in the clinic. Our work also builds a strong foundation for further evaluation of eNK-EXO in other solid tumor therapies.

Exosomes: A potential tool for immunotherapy of ovarian cancer

Ovarian cancer is a malignant tumor of the female reproductive system, with a very poor prognosis and high mortality rates. Chemotherapy and radiotherapy are the most common treatments for ovarian cancer, with unsatisfactory results. Exosomes are a subpopulation of extracellular vesicles, which have a diameter of approximately 30–100 nm and are secreted by many different types of cells in various body fluids. Exosomes are highly stable and are effective carriers of immunotherapeutic drugs. Recent studies have shown that exosomes are involved in various cellular responses in the tumor microenvironment, influencing the development and therapeutic efficacy of ovarian cancer, and exhibiting dual roles in inhibiting and promoting tumor development. Exosomes also contain a variety of genes related to ovarian cancer immunotherapy that could be potential biomarkers for ovarian cancer diagnosis and prognosis. Undoubtedly, exosomes have great therapeutic potential in the field of ovarian cancer immunotherapy. However, translation of this idea to the clinic has not occurred. Therefore, it is important to understand how exosomes could be used in ovarian cancer immunotherapy to regulate tumor progression. In this review, we summarize the biomarkers of exosomes in different body fluids related to immunotherapy in ovarian cancer and the potential mechanisms by which exosomes influence immunotherapeutic response. We also discuss the prospects for clinical application of exosome-based immunotherapy in ovarian cancer.

Longitudinal analysis of DC subsets in patients with ovarian cancer: Implications for immunotherapy

BackgroundThe use of circulating cDC1 to generate anti-cancer vaccines is among the most promising approaches to overcome the limited immunogenicity and clinical efficacy of monocyte-derived DC. However, the recurrent lymphopenia and the reduction of DC numbers and functionality in patients with cancer may represent an important limitation of such approach. In patients with ovarian cancer (OvC) that had received chemotherapy, we previously showed that cDC1 frequency and function were reduced.MethodsWe recruited healthy donors (HD, n=7) and patients with OvC at diagnosis and undergoing interval debulking surgery (IDS, n=6), primary debulking surgery (PDS, n=6) or at relapse (n=8). We characterized longitudinally phenotypic and functional properties of peripheral DC subsets by multiparametric flow cytometry.ResultsWe show that the frequency of cDC1 and the total CD141+ DC capacity to take up antigen are not reduced at the diagnosis, while their TLR3 responsiveness is partially impaired in comparison with HD. Chemotherapy causes cDC1 depletion and increase in cDC2 frequency, but mainly in patients belonging to the PDS group, while in the IDS group both total lymphocytes and cDC1 are preserved. The capacity of total CD141+ DC and cDC2 to take up antigen is not impacted by chemotherapy, while the activation capacity upon Poly(I:C) (TLR3L) stimulation is further decreased.ConclusionsOur study provides new information about the impact of chemotherapy on the immune system of patients with OvC and sheds a new light on the importance of considering timing with respect to chemotherapy when designing new vaccination strategies that aim at withdrawing or targeting specific DC subsets.

SAMHD1 expression modulates innate immune activation and correlates with ovarian cancer prognosis

PurposeSAMHD1 is a deoxynucleotide triphosphate (dNTP) triphosphohydrolase which has been proposed as a putative prognostic factor in haematological cancers and certain solid tumours, although with controversial data. Here, we evaluate SAMHD1 function in ovarian cancer, both in vitro and in ovarian cancer patients.MethodsSAMHD1 expression was downregulated in ovarian cancer cell lines OVCAR3 and SKOV3 by RNA interference. Gene and protein expression changes in immune signalling pathways were assessed. SAMHD1 expression in ovarian cancer patients was evaluated by immunohistochemistry and survival analysis was performed according to SAMHD1 expression.ResultsSAMHD1 knockdown induced a significant upregulation of proinflammatory cytokines concomitant to increased expression of the main RNA-sensors, MDA5 and RIG-I, and interferon-stimulated genes, supporting the idea that the absence of SAMHD1 promotes innate immune activation in vitro. To assess the contribution of SAMHD1 in ovarian cancer patients, tumours were stratified in SAMHD1-low and SAMHD1-high expressing tumours, resulting in significantly shorter progression free survival (PFS) and overall survival (OS) in SAMHD1-high expression subgroup (p=0.01 and 0.04, respectively).ConclusionsSAMHD1 depletion correlates with increased innate immune cell signalling in ovarian cancer cells. In clinical samples, SAMHD1-low expressing tumors showed increased progression free survival and overall survival irrespective of BRCA mutation status. These results point towards SAMHD1 modulation as a new therapeutic strategy, able to enhance innate immune activation directly in tumour cells, leading to improved prognosis in ovarian cancer.

Chemical immune conization of precancerous cervical lesions awakens immune cells and restores normal HPV negative and abnormal proliferation

BackgroundCervical cancer is one of the most common and deadly cancers in women, which is closely linked to the persistent infection of high-risk human papillomavirus (HPV). Current treatment of cervical cancer involves radical hysterectomy, radiotherapy, and chemotherapy or a combination.ObjectiveWe investigated if hapten-enhanced intratumoral chemotherapy (HEIC) was effective in boosting immunity for effective treatment of precancerous cervical lesions and HPV infection.Study designWe used single-cell RNA sequencing (scRNA-Seq) to obtain transcriptome profiles of 40,239 cells from biopsies of precancerous cervical lesions from the cervix directly from one patient before the start of HEIC and approximately 1 week after HEIC. The blood samples were taken at the same time as biopsies. We compared the expression characteristics of malignant epithelial cells and immune cells, including epithelial cells, endothelial cells (ECs), fibroblasts, mural cells, T cells, B cells, T and NK neutrophils, mast cells, microparticles (MPs), and platelets, as well as the dynamic changes in cell percentage and cell subtype heterogeneity.ResultsIntratumoral injection of chemotherapy drug plus hapten induces an acute immune response in precancerous cervical lesions with HPV and further awakens immune cells to prevent the abnormal proliferation of the precancerous cells.ConclusionHEIC provides a potential treatment method for cervical cancer and HPV infection tailored to each patient’s condition.

Complete and early response to cemiplimab associated to severe immune toxicity in advanced cervical cancer: a case report

Cervical cancer (CC) is the second most commonly diagnosed cancer and the third leading cause of cancer death among females. The options of treatment for recurrent/advanced CC are limited and patients experiencing recurrence after first line platinum-based chemotherapy have a poor prognosis. In this context, immune checkpoint inhibitors (ICI)s antagonizing PD-1 and programmed death-ligand 1 (PD-L1) have profoundly changed the treatment scenario and outcomes in CC in the first or subsequent lines both as monotherapies or in combination with chemotherapy or other ICIs. Herein, we report the clinical case of a 74-year-old woman with metastatic CC with negative tumor PD-L1 expression who having disease progression after first-line of systemic treatment with platinum, thus undergoing to anti-PD-1 namely cemiplimab. The patient achieved a surprising, fast and complete metabolic response to cemiplimab immediately discontinued after only two cycles due to the onset of rare and severe immune-related adverse events (irAE)s such cardiovascular toxicity and hypertransaminasemia. Despite this, thirteen months later, the patient remains disease-free despite cemiplimab was withdrawn.

KLF14 activates the JNK-signaling pathway to induce S-phase arrest in cervical cancer cells

ObjectiveTo explore the role of Krüppel-like factor 14 (KLF14) and its underlying mechanism(s) of action in cell-cycle regulation in cervical cancer.MethodsLentiviral infection was used to construct KLF14, KLF14 zinc-finger structural mutations, and empty vector controls in SiHa and HeLa cervical cancer cells. The effect of KLF14 on cervical cancer cell cycle was detected by flow cytometry. The effect of KLF14 on the expression of cyclin-dependent kinase 2 (CDK2), cyclin A2 (CCNA2), and MAPK signalling pathway-related molecules was detected by fluorescence quantitative RT-PCR (qRT-PCR) and western blot. Cervical cancer cells were treated with JNK-pathway inhibitors/agonists before we assessed changes in the cell cycle and the expression of the CDK2, CCNA2, and p-JNK/JNK. Subcutaneous xenograft studies to explore the effects of KLF14 on cervical cancer cell proliferation in vivo, and western blotting was implemented to measure the expression of CCNA2, CDK2, and the activation levels of the MAPK-signaling pathway proteins in tumours.ResultsThe proportion of cells in the S phase was increased in the KLF14-overexpressing group compared with the control group (P<0.001); CDK2, CCNA2, and p-JNK/JNK expression levels were elevated in the KLF14-overexpressing group relative to the control group (all P<0.05). When JNK-pathway activation was inhibited/promoted, the proportion of cells in the S phase was reduced/increased (P<0.05) and CDK2 and CCNA2 expression levels were reduced/decreased, respectively (all P<0.05). Vivo experiments revealed that KLF14 inhibited cervical cancer cell proliferation (P<0.01) and that p-JNK/JNK, CDK2, and CCNA2 expression levels were augmented in tumours in the overexpression group (P<0.01).ConclusionKLF14 induced S-phase arrest in cervical cancer cells and inhibited the proliferation of cervical cancer cells in vivo; the induction of S-phase arrest was related to its zinc-finger structure. KLF14 also activated the JNK pathway to induce S-phase arrest and promote the expression of CDK2 and CCNA2. In summary, KLF14 activates the JNK-signaling pathway to induce S-phase arrest in cervical cancer cells

γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids

Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies. In addition to αβ T cells and natural killer (NK) cells, γδ T cells represent an immune cell population with significant therapeutic potential against both hematologic and solid tumours. To evaluate the efficacy of γδ T cells in cervical cancer treatment, we generated patient-derived healthy and cancer ectocervical organoids. Furthermore, we examined transformed healthy organoids, expressing HPV16 oncogenes E6 and E7. We analysed the effector function of in vitro expanded γδ T cells upon co-culture with organoids. Our findings demonstrated that healthy cervical organoids were less susceptible to γδ T cell-mediated cytotoxicity compared to HPV-transformed organoids and cancerous organoids. To identify the underlying pathways involved in this observed cytotoxicity, we performed bulk-RNA sequencing on the organoid lines, revealing differences in DNA-damage and cell cycle checkpoint pathways, as well as transcription of potential γδ T cell ligands. We validated these results using immunoblotting and flow cytometry. We also demonstrated the involvement of BTN3A1 and BTN2A1, crucial molecules for γδ T cell activation, as well as differential expression of PDL1/CD274 in cancer, E6/E7+ and healthy organoids. Interestingly, we observed a significant reduction in cytotoxicity upon blocking MSH2, a protein involved in DNA mismatch-repair. In summary, we established a co-culture system of γδ T cells with cervical cancer organoids, providing a novel in vitro model to optimize innovative patient-specific immunotherapies for cervical cancer.

An Update on Human Papilloma Virus Vaccines: History, Types, Protection, and Efficacy

Human papillomavirus (HPV) is the most common sexually transmitted agent worldwide. Early prevention with HPV vaccination is a safe and effective method against this disease. HPV vaccines provided more protection against several oncogenic HPV strains. Three prophylactic HPV vaccines have been approved to target high-risk HPV types and protect against HPV-related disorders. These existing vaccines are based on the recombinant DNA technology and purified L1 protein that is assembled to form HPV empty shells. The prophylactic vaccines are highly immunogenic and can induce production of specific neutralizing antibodies. However, therapeutic vaccines are different from these prophylactic vaccines. They induced cell-mediated immunity against transformed cells, instead of neutralizing antibodies. The second generation of prophylactic HPV vaccines, made from alternative viral components using cost-effective production strategies, is undergoing clinical evaluation. The purpose of this review is to provide a complete and up-to-date review of the types of HPV vaccines and the efficiency of each of them for readers.

Single-cell RNA-seq reveals FGF12 as a prognostic biomarker in low-grade endometrial stromal sarcoma

BackgroundLow-grade endometrial stromal sarcoma (LG-ESS) is a rare uterine malignancy characterized by its complex tumor microenvironment (TME) and high recurrence rates, posing challenges to accurate prognosis and effective treatment. Identifying prognostic biomarkers is essential for improving patient stratification and guiding therapeutic strategies.MethodsUsing single-cell transcriptome analysis combined with H&E and multiplex immunofluorescence staining, we identified a subpopulation of tumor cells in LG-ESS and further validated the association of this subpopulation and its characteristic genes with LG-ESS prognosis by molecular characterization and bulk transcriptome data.ResultsOur analysis reveals multiple cellular subpopulations within the tumor tissue, particularly a tumor cell subpopulation among them which is associated with poor prognosis. Originating from normal stromal fibroblasts, this subpopulation appears to play a crucial role in TME remodeling, smooth muscle cell behavior, and potentially in tumorigenesis and metastasis. Of particular interest in this subpopulation is the highly expressed FGF12 gene, which is significantly associated with a shortened survival in ESS, highlighting its potential as a prognostic biomarker.ConclusionOur study reveals the complexity of TME within the LG-ESS and highlights the role that tumor cell subpopulations play in disease progression and patient prognosis. The identification of FGF12 as a prognostic biomarker suggests a new approach for the personalized treatment and prognosis monitoring of patients.

Knowledge mapping and visualization of trends in immunotherapy for ovarian cancer over the past five years: a bibliometric analysis

BackgroundThis study conducts a bibliometric literature analysis to explore trends in immunotherapy for ovarian cancer from 2019 to 2023.MethodsAn extensive online literature search was conducted in the Web of Science Core Collection database to identify English-language articles and reviews related to “trends in immunotherapy”, and “ovarian cancer”. statistical analysis was performed using VOSviewer to visualize and compare nations, institutions, and journals simultaneously.ResultsOur findings highlight contributions by 118 nations, led by the People’s Republic of China with 3,167 contributions; Germany followed with 558 and Italy having 547. Of all publications made between 2019-2023, “Frontiers Immunology” had the most publications with 546 total records followed by “cancers “, and “frontiers in oncology” being the most heavily relied upon categories. Annually publication trends increased until 2022 but then declined considerably as a peak of highly-cited papers occurring between 2019 and 2022.ConclusionsOur bibliometric analysis not only maps the evolution of immunotherapy research in ovarian cancer but also provides actionable insights for advancing scientific progress. By identifying emerging trends and key areas, future research can strategically enhance treatment strategies and outcomes for ovarian cancer patients.

Current status and future directions for the development of human papillomavirus vaccines

The development of human papillomavirus (HPV) vaccines has made substantive progress, as represented by the approval of five prophylactic vaccines since 2006. Generally, the deployment of prophylactic HPV vaccines is effective in preventing newly acquired infections and incidences of HPV-related malignancies. However, there is still a long way to go regarding the prevention of all HPV infections and the eradication of established HPV infections, as well as the subsequent progression to cancer. Optimizing prophylactic HPV vaccines by incorporating L1 proteins from more HPV subtypes, exploring adjuvants that reinforce cellular immune responses to eradicate HPV-infected cells, and developing therapeutic HPV vaccines used either alone or in combination with other cancer therapeutic modalities might bring about a new era getting closer to the vision to get rid of HPV infection and related diseases. Herein, we summarize strategies for the development of HPV vaccines, both prophylactic and therapeutic, with an emphasis on the selection of antigens and adjuvants, as well as implications for vaccine efficacy based on preclinical studies and clinical trials. Additionally, we outline current cutting-edge insights on formulation strategies, dosing schedules, and age expansion among HPV vaccine recipients, which might play important roles in addressing barriers to vaccine uptake, such as vaccine hesitancy and vaccine availability.

Sequencing-based transcriptome analysis reveals diversification of immune response- and angiogenesis-related expression patterns of early-stage cervical carcinoma as compared with high-grade CIN

BackgroundMolecular diversity of virus-associated cervical cancer remains a relatively underexplored issue, and interrelations of immunologic and angiogenic features during the establishment of a particular landscape of the cervical cancer microenvironment are not well-characterized, especially for its earliest clinical stages, although this may provide insight into the mechanisms behind the differences in tumor aggressiveness, treatment responsiveness and prognosis. In this research, we were aimed at identifying transcriptomic landscapes of early-stage cervical carcinoma that differ substantially in their immune-related characteristics, patterns of signaling pathways and composition of the microenvironment in comparison with immediate precursor (intraepithelial) lesions.MethodsWe performed the Illumina platform-based RNA sequencing using a panel of fresh tissue samples that included human papillomavirus-positive cervical intraepithelial neoplastic lesions (CIN), invasive squamous carcinoma of the cervix of FIGO IA1-IIB stages, and morphologically normal epithelium. The derived transcriptomic profiles were bioinformatically analyzed and compared by patterns of signaling pathway activation, distribution of tumor-infiltrating cell populations, and genomic regions involved.ResultAccording to hierarchical cluster analysis of the whole-transcriptome profiles, tissue samples were distributed between three groups, or gene expression patterns (the one comprising most pre-cancer cases and the other two encompassing mostly early-stage invasive cancer cases). Differentially expressed genes were retrieved in each intergroup pairwise comparison followed by Gene Ontology analysis. Gene set enrichment analysis of the two groups of tumor samples in comparison with the CIN group identified substantial differences in immunological and angiogenic properties between tumorous groups suggesting the development of different molecular phenotypes. Cell composition analysis confirmed the diverse changes in the abundancies of immune and non-immune populations and, accordingly, different impacts of the immune and stromal compartments on the tumor microenvironment in these two groups of tumors compared to CIN. Positional gene expression analysis demonstrated that the identified transcriptomic differences were linked to different chromosomal regions and co-localized with particular gene families implicated in immune regulation, inflammation, cell differentiation, and tumor invasion.ConclusionsOverall, detection of different transcriptomic patterns of invasive cervical carcinoma at its earliest stages supports the diverse impacts of immune response- and angiogenesis-related mechanisms on the onset of tumor invasion and progression. This may provide new options for broadening the applicability and increasing the efficiency of target anti-angiogenic and immune-based therapy of virus-associated cervical carcinoma.

The anti-PD-1 era of cervical cancer: achievement, opportunity, and challenge

Cervical cancer is one of the three major female gynecological malignancies, becoming a major global health challenge. Although about 90% of early-stage patients can be cured by surgery, advanced-stage patients still need new treatment methods to improve their efficacy, especially for those with recurrence and metastasis tumors. Anti-PD-1 is currently the most widely used immune checkpoint inhibitor, which has revolutionized cancer therapy for different types of cancer. Pembrolizumab has been approved for second-line treatment of R/M CC but has a modest overall response rate of about 15%. Therefore, multiple types of anti-PD-1 have entered clinical trials successively and evaluated the efficacy in combination with chemotherapy, targeted therapy, and immunotherapy. At the same time, the dual specific antibody of PD-1/CTLA-4 was also used in clinical trials of cervical cancer, and the results showed better than anti-PD-1 monotherapy. In addition, anti-PD-1 has also been shown to sensitize radiotherapy. Therefore, understanding the current research progress of anti-PD-1 will better guide clinical application. This review summarizes ongoing clinical trials and published studies of anti-PD-1 monotherapy and combination therapy in the treatment of cervical cancer, as well as discusses the potential molecular biological mechanisms of combination, aiming to provide the basic evidence for support anti-PD-1 in the treatment of cervical cancer and new insights in combination immunotherapy.

HPV16 E6/E7 -based mRNA vaccine is therapeutic in mice bearing aggressive HPV-positive lesions

HPV (Human papillomavirus) affects 600,000 people worldwide each year. Almost all cervical cancers are associated with a past HPV infection. In particular, the positivity to the high-risk type HPV16 is detected in most of the invasive cervical cancers. FDA has approved prophylactic vaccines that protect against new HPV16 infections, but do not induce immunity in those patients with established infections or neoplasms. To date, no therapeutic vaccine targeting HPV16-associated lesions has been authorized. We have developed an mRNA-based vaccine against the HPV16 late oncoproteins E6 and E7, which are abundantly and exclusively expressed in high-grade squamous intraepithelial lesions (HSILs), a stage of the cervical disease that precedes the progression to carcinoma. Our in vitro and in vivo studies demonstrated that the translated mRNA is functional and elicits an antigen-specific adaptive immune response. Upon immunization with the vaccine, mice with HPV16+ lesions exhibited tumor growth inhibition, extension of lifespan, and development of a protective immune memory. In light of these results and the remarkable clinical success of mRNA vaccines against SARS-CoV2, we believe that our mRNA-based therapeutic vaccine has the potential to offer a non-invasive treatment alternative to the current standard of care for HPV16+ HSILs.

The abscopal effect of immune-radiation therapy in recurrent and metastatic cervical cancer: a narrative review

Despite human papillomavirus vaccination and screening, in about 5% of cases, cervical cancer (CC) is discovered at an initial metastatic stage. Moreover, nearly one-third of patients with locally advanced CC (LACC) will have a recurrence of their disease during follow-up. At the stage of recurrent or metastatic CC, there are very few treatment options. They are considered incurable with a very poor prognosis. For many years, the standard of care was the combination of platinum-based drug and paclitaxel with the possible addition of bevacizumab. The most recent years have seen the development of the use of immune checkpoint inhibitors (ICIs) (pembrolizumab, cemiplimab and others) in patients with CC. They have shown long term responses with improved overall survival of patients in 1st line (in addition to chemotherapy) or 2nd line (as monotherapy) treatment. Another emerging drug is tisotumab vedotin, an antibody-drug conjugate targeting tissue factor. Radiation therapy (RT) often has a limited palliative indication in metastatic cancers. However, it has been observed that RT can induce tumor shrinkage both in distant metastatic tumors beyond the radiation field and in primary irradiated tumors. This is a rarely observed phenomenon, called abscopal effect, which is thought to be related to the immune system and allows a tumor response throughout the body. It would be the activation of the immune system induced by the irradiation of cancer cells that would lead to a specific type of apoptosis, the immunogenic cell death. Today, there is a growing consensus that combining RT with ICIs may boost abscopal response or cure rates for various cancers. Here we will review the potential abscopal effect of immune-radiation therapy in metastatic cervical cancer.

A novel DNA damage repair-related gene signature predicting survival, immune infiltration and drug sensitivity in cervical cancer based on single cell sequencing

BackgroundAberrant DNA damage repair (DDR) is one of the hallmarks of tumors, and therapeutic approaches targeting this feature are gaining increasing attention. This study aims to develop a signature of DDR-related genes to evaluate the prognosis of cervical cancer (CC).MethodsDifferentially expressed genes were identified between high and low DDR groups of cells from the single-cell RNA sequencing dataset GSE168652 based on DDR scores. Using the ssGSEA and WGCNA methods, DDR-related differentially expressed genes were identified from different patients within the TCGA-CESC cohort. Using Cox analysis and LASSO regression analysis, a DDR-related gene signature was constructed based on the intersection of two groups of differentially expressed genes and DDR-related genes from WGCNA, and validated in GSE52903. Immune cell infiltration analysis, mutation analysis, survival analysis, drug sensitivity analysis, etc., were performed in different groups which were established based on the DDR gene signature scoring. A key gene affecting prognosis was selected and validated through biological experiments such as wound healing, migration, invasion, and comet assays.ResultsA novel DDR-related signature was constructed and the nomogram results showed this signature performed better in predicting prognosis than other clinical features for CC. The high DDR group exhibited poorer prognosis, weaker immune cell infiltration in the immune microenvironment, lower expression of immune checkpoint-related genes, lower gene mutation frequencies and more sensitivity to drugs such as BI.2536, Bleomycin and etc. ITGB1, ZC3H13, and TOMM20 were expressed at higher levels in CaSki and HeLa cells compared to ECT1 cells. Compared with the native CaSki and HeLa cells, the proliferation, migration, invasion and DDR capabilities of CaSki and HeLa cell lines with ITGB1 suppressed expression were significantly decreased.ConclusionThe 7 DDR-related gene signature was an independent and powerful prognostic biomarker that might effectively evaluate the prognosis of CC and provide supplementary information for a more personalized evaluation and precision therapy. ITGB1 was a potential candidate gene that may affect the DDR capacity of CC cells, and its mechanism of action was worth further in-depth study.

T cell immunotherapy for cervical cancer: challenges and opportunities

Cancer cellular immunotherapy has made inspiring therapeutic effects in clinical practices, which brings new hope for the cure of cervical cancer. CD8+T cells are the effective cytotoxic effector cells against cancer in antitumor immunity, and T cells-based immunotherapy plays a crucial role in cellular immunotherapy. Tumor infiltrated Lymphocytes (TIL), the natural T cells, is approved for cervical cancer immunotherapy, and Engineered T cells therapy also has impressive progress. T cells with natural or engineered tumor antigen binding sites (CAR-T, TCR-T) are expanded in vitro, and re-infused back into the patients to eradicate tumor cells. This review summarizes the preclinical research and clinical applications of T cell-based immunotherapy for cervical cancer, and the challenges for cervical cancer immunotherapy.

Stapled peptide PROTAC induced significantly greater anti-PD-L1 effects than inhibitor in human cervical cancer cells

IntroductionImmune checkpoint inhibitors (ICIs) are monoclonal antibodies that target immune checkpoints that suppress immune cell activity. Low efficiency and high resistance are currently the main barriers to their clinical application. As a representative technology of targeted protein degradation, proteolysis-targeting chimeras (PROTACs) are considered to have potential for addressing these limitations.MethodsWe synthesized a stapled peptide-based PROTAC (SP-PROTAC) that specifically targeted palmitoyltransferase ZDHHC3 and resulted in the decrease of PD-L1 in human cervical cancer cell lines. Flow cytometry, confocal microscopy, protein immunoblotting, Cellular Thermal Shift Assay (CETSA), and MTT assay analyses were conducted to evaluate the effects of the designed peptide and verify its safety in human cells.ResultsIn cervical cancer celllines C33A and HeLa, the stapled peptide strongly downregulated PD-L1 to < 50% of baseline level at 0.1 μM. DHHC3 expression decreased in both dosedependentand time-dependent manners. MG132, the proteasome inhibitor, can alleviate the SP-PROTAC mediated degradation of PD-L1 in human cancer cells. In a co-culture model of C33A and T cells, treatment with the peptide induced IFN-γ and TNF-α release in a dose-dependent manner by degrading PD-L1. These effects were more significant than that of the PD-L1 inhibitor, BMS-8.ConclusionsCells treated with 0.1 μM of SP-PROTAC or BMS-8 for 4 h revealed that the stapled peptide decreased PD-L1 more effectively than BMS-8. DHHC3-targeting SP-PROTAC decreased PD-L1 in human cervical cancer more effectively than the inhibitor BMS-8.

CD44 targeted delivery of oncolytic Newcastle disease virus encapsulated in thiolated chitosan for sustained release in cervical cancer: a targeted immunotherapy approach

IntroductionCervical cancer accounts for one of most common cancers among women of reproductive age. Oncolytic virotherapy has emerged as a promising immunotherapy modality but it comes with several drawbacks that include rapid clearance of virus from body due to immune-neutralization of virus in host. To overcome this, we encapsulated oncolytic Newcastle disease virus (NDV) in polymeric thiolated chitosan nanoparticles. For active targeting of virus loaded nanoformulation against CD44 (cluster of differentiation 44) receptors which are overly expressed on cancer cells, these nanoparticles were surface functionalized with hyaluronic acid (HA).MethodsUsing half dose of NDV (TCID50 (50% tissue culture infective dose) single dose 3 × 105), virus loaded nanoparticles were prepared by green synthesis approach through ionotropic gelation method. Zeta analysis was performed to analyse size and charge on nanoparticles. Nanoparticles (NPs) shape and size were analysed by SEM (scanning electron microscope) and TEM (transmission electron microscope) while functional group identification was done by FTIR (fourier transform infrared) and XRD (X-ray diffraction). Viral quantification was done by TCID50 and Multiplicity of infection (MOI) determination while oncolytic potential of NPs encapsulated virus was analysed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and cell morphology analysis.ResultsZeta analysis showed that average size of NDV loaded thiolated chitosan nanoparticles surface functionalized with HA (HA-ThCs-NDV) was 290.4nm with zeta potential of 22.3 mV and 0.265 PDI (polydispersity index). SEM and TEM analysis showed smooth surface and spherical features of nanoparticles. FTIR and XRD confirmed the presence of characteristic functional groups and successful encapsulation of the virus. In vitro release showed continuous but sustained release of NDV for up to 48 hours. TCID50 for HA-ThCs-NDV nanoparticles was 2.63x 106/mL titter and the nanoformulation exhibited high oncolytic potential in cell morphology analysis and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay as compared to naked virus, in dose dependent manner.DiscussionThese findings suggest that virus encapsulation in thiolated chitosan nanoparticles and surface functionalization with HA is not only helpful in achieving active targeting while masking virus from immune system but, it also gives sustained release of virus in tumor microenvironment for longer period of time that increases bioavailability of virus.

Microbiome analysis of Brazilian women cervix reveals specific bacterial abundance correlation to RIG-like receptor gene expression

The relationship among microbiome, immunity and cervical cancer has been targeted by several studies, yet many questions remain unanswered. We characterized herein the virome and bacteriome from cervical samples and correlated these findings with innate immunity gene expression in a Brazilian convenience sample of HPV-infected (HPV+) and uninfected (HPV-) women. For this purpose, innate immune gene expression data were correlated to metagenomic information. Correlation analysis showed that interferon (IFN) is able to differentially modulate pattern recognition receptors (PRRs) expression based on HPV status. Virome analysis indicated that HPV infection correlates to the presence of Anellovirus (AV) and seven complete HPV genomes were assembled. Bacteriome results unveiled that vaginal community state types (CST) distribution was independent of HPV or AV status, although bacterial phyla distribution differed between groups. Furthermore, TLR3 and IFNαR2 levels were higher in the Lactobacillus no iners-dominated mucosa and we detected correlations among RIG-like receptors (RLR) associated genes and abundance of specific anaerobic bacteria. Collectively, our data show an intriguing connection between HPV and AV infections that could foster cervical cancer development. Besides that, TLR3 and IFNαR2 seem to create a protective milieu in healthy cervical mucosa (L. no iners-dominated), and RLRs, known to recognize viral RNA, were correlated to anaerobic bacteria suggesting that they might be related to dysbiosis.

Case report: Autoimmune encephalitis with multiple auto-antibodies with reversible splenial lesion syndrome and bilateral ovarian teratoma

BackgroundReversible splenial lesion syndrome (RESLES) is a spectrum of disease radiologically characterized by reversible lesions caused by multiple factors, primarily involving the splenium of the corpus callosum (SCC). The most common causes of RESLES include infection, antiepileptic drug use and withdrawal, and severe metabolic disorders. Nevertheless, cases of autoimmune encephalitis (AE) are uncommon.Case presentationA 26-year-old female computer programming engineer with no previous medical or psychiatric history reported to the psychiatric hospital due to a 3-day episode of irritability, babbling, limb stiffness, sleepwalking, hallucinations, and paroxysmal mania. Brain MRI revealed abnormal signals of the SCC. Lumbar puncture was performed and further testing for auto-antibodies was conducted in both the CSF and serum. CSF of the patient was positive for anti-NMDAR (titer of 1:3.2) antibodies, and serum was also positive for anti-NMDAR (titer of 1:32) as well as mGluR5 (titer of 1:10) antibodies. Enhanced CT of the pelvis showed an enlarged pelvic mass; bilateral ovarian teratomas (mature teratoma and immature teratoma) were evaluated, which were pathologically confirmed after transabdominal left adnexal resection, right ovarian biopsy, and ovarian cystectomy. The patient considerably improved after intravenous administration of steroids, immunoglobulin, oral prednisone, surgical treatment, and chemotherapy. A follow-up MRI revealed completely resolved lesions. During a 3-month follow-up, the patient experienced complete resolution of symptoms without any sign of recurrence and tumors. The titer of the anti-NMDAR antibody decreased to 1:10 in serum.ConclusionHerein, we report a rare case of AE with overlapping auto-antibodies, along with RESLES and bilateral ovarian teratomas. The current case provides the possibility of the concurrence of mGluR5 antibodies in anti-NMDAR encephalitis. However, the underlying mechanism remains elusive. Furthermore, we provide additional evidence that overlapping antibodies-related pathology may be one of the many causes of RESLES. Nonetheless, caution should be observed in interpreting the observation, considering that this is a single-case study.

Genetic variants of LRRC8C, OAS2, and CCL25 in the T cell exhaustion-related genes are associated with non-small cell lung cancer survival

BackgroundT cell exhaustion is a state in which T cells become dysfunctional and is associated with a decreased efficacy of immune checkpoint inhibitors. Lung cancer has the highest mortality among all cancers. However, the roles of genetic variants of the T cell exhaustion-related genes in the prognosis of non-small cell lung cancer (NSCLC) patients has not been reported.MethodsWe conducted a two-stage multivariable Cox proportional hazards regression analysis with two previous genome-wide association study (GWAS) datasets to explore associations between genetic variants in the T cell exhaustion-related genes and survival of NSCLC patients. We also performed expression quantitative trait loci analysis for functional validation of the identified variants.ResultsOf all the 52,103 single nucleotide polymorphisms (SNPs) in 672 T cell exhaustion-related genes, 1,721 SNPs were found to be associated with overall survival (OS) of 1185 NSCLC patients of the discovery GWAS dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and 125 of these 1,721 SNPs remained significant after validation in an additional independent replication GWAS dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. In multivariable stepwise Cox model analysis, three independent SNPs (i.e., LRRC8C rs10493829 T>C, OAS2 rs2239193 A>G, and CCL25 rs3136651 T>A) remained significantly associated with OS with hazards ratios (HRs) of 0.86 (95% confidence interval (CI) = 0.77-0.96, P = 0.008), 1.48 (95% CI = 1.18-1.85, P < 0.0001) and 0.78 (95% CI = 0.66-0.91, P = 0.002), respectively. Further combined analysis for these three SNPs suggested that an unfavorable genotype score was associated with a poor OS and disease-specific survival. Expression quantitative trait loci analysis suggested that the LRRC8C rs10493829 C allele was associated with elevated LRRC8C mRNA expression levels in normal lymphoblastoid cells, lung tissue, and whole blood.ConclusionOur findings suggested that these functional SNPs in the T cell exhaustion-related genes may be prognostic predictors for survival of NSCLC patients, possibly via a mechanism of modulating corresponding gene expression.

Therapeutic implications of the tumor microenvironment in ovarian cancer patients receiving PD-1/PD-L1 therapy

Epithelial ovarian cancer (EOC) ranks as the second most common cause of gynecologic cancer death. The conventional treatment for patients with EOC is postoperative therapy along with platinum chemotherapy. However, a more efficient treatment regimen is of great need for these patients diagnosed with advanced disease (FIGO stages III–IV), whose survival is approximately 29%. Immunotherapy seems to be an encouraging therapeutic strategy for EOC. Given the crucial role in the complicated interactions between tumor cells and other cells, the tumor microenvironment (TME) influences the response to immunotherapy. In this review, we discuss feasible strategies for EOC immunotherapy by exploiting the reciprocity of cancer cells and the constituents of the TME.

The role of interferons in ovarian cancer progression: Hinderer or promoter?

Ovarian cancer (OC) is a common gynecologic malignancy with poor prognosis and high mortality. Changes in the OC microenvironment are closely related to the genesis, invasion, metastasis, recurrence, and drug-resistance. The OC microenvironment is regulated by Interferons (IFNs) known as a type of important cytokines. IFNs have a bidirectional regulation for OC cells growth and survival. Meanwhile, IFNs positively regulate the recruitment, differentiation and activation of immune cells. This review summarizes the secretion and the role of IFNs. In particular, we mainly elucidate the actions played by IFNs in various types of therapy. IFNs assist radiotherapy, targeted therapy, immunotherapy and biotherapy for OC, except for some IFN pathways that may cause chemo-resistance. In addition, we present some advances in OC treatment with the help of IFN pathways. IFNs have the ability to powerfully modulate the tumor microenvironment and can potentially provide new combination strategies for OC treatment.

Case report: Variable response to immunotherapy in ovarian cancer: Our experience within the current state of the art

Despite recent advances in ovarian cancer (OC) treatment, including the introduction of bevacizumab and PARP-inhibitors, OC remains a lethal disease. Other therapeutic options are being explored, such as immunotherapy (IT), which has been proved effective in many solid tumors. Findings about tumor-infiltrating cytotoxic and regulatory T cells, together with the expression of PD-1 on immune cells and of PD-L1 on tumor cells, gave the rationale for an attempt to the use of IT also in OC. We treated two patients with avelumab, an anti-PD-L1 monoclonal antibody, after the first line of chemotherapy: Patient A underwent 19 cycles of maintenance therapy with avelumab with a disease-free interval of 12 months, whereas patient B showed a slight progression of disease after only eight cycles. A higher PD-L1 expression in tumor cells of patient A was detected. She also underwent a genomic assessment that described the presence of a high Tumor Mutational Burden (TMB) and a status of Loss of Heterozygosity (LoH). This different response to the same treatment puts in evidence that some genomic and immune features might be investigated.

Dendritic Cell Vaccines in Ovarian Cancer

Ovarian cancer (OC) is one of the most lethal malignant gynecologic tumors, characterized by an uncertain presentation and poor outcomes. With or without neoadjuvant chemotherapy, surgery followed by platinum-based chemotherapy and maintenance therapy are the basis for the treatment of ovarian cancer patients, but the outcome is still highly restricted by their advanced stage when diagnosed and high recurrence rate after chemotherapy. To enhance the anti-tumor effect and postpone recurrence, anti-VEGF agents and PARP inhibitors are suggested as maintenance therapy, but the population that can benefit from these treatments is small. Based on the interactions of immune cells in the tumor microenvironment, immunotherapies are being explored for ovarian cancer treatment. Disappointingly, the immune checkpoint inhibitors show relatively low responses in ovarian cancer. As shown in several studies that have uncovered a relationship between DC infiltration and outcome in ovarian cancer patients, dendritic cell (DC)-based treatments might have a potential effect on ovarian cancer. In this review, we summarize the functions of dendritic cells (DCs) in the tumor microenvironment, as well as the responses and drawbacks of existing clinical studies to draw a comprehensive picture of DC vaccine treatment in ovarian cancer and to discuss the promising future of immune biomarkers.

Quantification of Bevacizumab Activity Following Treatment of Patients With Ovarian Cancer or Glioblastoma

Highly sensitive reporter-gene assays have been developed that allow both the direct vascular endothelial growth factor (VEGF) neutralizing activity of bevacizumab and the ability of bevacizumab to activate antibody dependent cellular cytotoxicity (ADCC) to be quantified rapidly and in a highly specific manner. The use of these assays has shown that in 46 patients with ovarian cancer following four cycle of bevacizumab treatment, and in longitudinal samples from the two patients that respond to bevacizumab therapy from a small cohort of patients with glioblastoma, that there is a reasonably good correlation between bevacizumab drug levels determined by ELISA and bevacizumab activity, determined using either the VEGF-responsive reporter gene, or the ADCC assays. One of the two primary non-responders with glioblastoma exhibited high levels of ADCC activity suggesting reduced bevacizumab Fc engagement

Immunotherapy for Ovarian Cancer: Adjuvant, Combination, and Neoadjuvant

Ovarian cancer is the most lethal gynecologic malignancy. Surgery and chemotherapy are the primary treatments for ovarian cancer; however, patients often succumb to recurrence with chemotherapeutic resistance within several years after the initial treatment. In the past two decades, immunotherapy has rapidly developed, and has revolutionized the treatment of various types of cancer. Despite the fact that immunotherapy response rates among ovarian cancer patients remain modest, treatment with immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR)- and TCR-engineered T cells is rapidly developing. Therapeutic efficiency could be improved significantly if immunotherapy is included as an adjuvant therapy, in combination with chemotherapy, radiation therapy, and the use of anti-angiogenesis drugs, and poly ADP ribose polymerase inhibitors (PARPi). Newly developed technologies that identify therapeutic targets, predict treatment efficacy, rapidly screen potential immunotherapy drugs, provide neoadjuvant immunotherapy, and utilize nanomedicine technology provide new opportunities for the treatment of ovarian cancer, and have the potential to prolong patient survival. However, important issues that may hinder the efficacy of such approaches, including hyperprogressive disease (HPD), immunotherapy-resistance, and toxicity of the treatments, including neurotoxicity, must be taken into account and addressed for these therapies to be effective.

The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models

Particular interest to harness the innate immune system for cancer immunotherapy is fueled by limitations of immune checkpoint blockade. Plasmacytoid dendritic cells (pDC) are detected in a variety of solid tumors and correlate with poor clinical outcome. Release of type I interferons in response to toll-like-receptor (TLR)7 and TLR9 activation is the pDC hallmark. Mouse and human pDC differ substantially in their biology concerning surface marker expression and cytokine production. Here, we employed humanized mouse models (HIS) to study pDC function. We performed a comprehensive characterization of transgenic, myeloid-enhanced mouse strains (NOG-EXL and NSG-SGM3) expressing human interleukin-3 (hIL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) using identical humanization protocols. Only in HIS-NOG-EXL mice sufficient pDC infiltration was detectable. Therefore, we selected this strain for subsequent tumor studies. We analyzed pDC frequency in peripheral blood and tumors by comparing HIS-NOG-EXL with HIS-NOG mice bearing three different ovarian and breast tumors. Despite the substantially increased pDC numbers in peripheral blood of HIS-NOG-EXL mice, we detected TLR7/8 agonist responsive and thus functional pDCs only in certain tumor models independent of the mouse strain employed. However, HIS-NOG-EXL mice showed in general a superior humanization phenotype characterized by reconstitution of different myeloid subsets, NK cells and B cells producing physiologic IgG levels. Hence, we provide first evidence that the tumor milieu but not genetically introduced cytokines defines intratumoral (i.t.) frequencies of the rare pDC subset. This study provides model systems to investigate

CTL Attenuation Regulated by PS1 in Cancer-Associated Fibroblast

Clinically relevant body composition phenotypes are associated with distinct circulating cytokine and metabolomic milieus in epithelial ovarian cancer patients

IntroductionPreclinical evidence suggests that host obesity is associated with tumor progression due to immuno-metabolic dysfunction, but the impact of obesity on immunity and clinical outcomes in patients is poorly understood, with some studies suggesting an obesity paradox. We recently reported that high-adiposity and low-muscle body composition phenotypes are associated with striking increases in epithelial ovarian cancer (EOC) mortality and we observed no evidence of an obesity paradox. However, whether at-risk versus optimal body composition phenotypes are associated with distinct immuno-metabolic milieus remains a fundamental gap in knowledge. Herein, we defined differentially abundant circulating immuno-metabolic biomarkers according to body composition phenotypes in EOC.MethodsMuscle and adiposity cross-sectional area (cm2) was assessed using CT images from 200 EOC patients in The Body Composition and Epithelial Ovarian Cancer Survival Study at Roswell Park. Adiposity was dichotomized as low versus high; patients with skeletal muscle index (SMI) <38.5 (muscle cm2/height m2) were classified as low SMI (sarcopenia). Joint-exposure phenotypes were categorized as: Fit (normal SMI/low-adiposity), Overweight/Obese (normal SMI/high-adiposity), Sarcopenia/Obese (low SMI/high adiposity), and Sarcopenia/Cachexia (low SMI/low-adiposity). Treatment-naïve serum samples were assessed using Biocrates MxP Quant 500 for targeted metabolomics and commercially available Luminex kits for adipokines and Th1/Th2 cytokines. Limma moderated T-tests were used to identify differentially abundant metabolites and cytokines according to body composition phenotypes.ResultsPatients with ‘risk’ phenotypes had significantly increased abundance of metabolites and cytokines that were unique according to body composition phenotype. Specifically, the metabolites and cytokines in increased abundance in the at-risk phenotypes are implicated in immune suppression and tumor progression. Conversely, increased abundance of lauric acid, IL-1β, and IL-2 in the Fit phenotype was observed, which have been previously implicated in tumor suppression and anti-tumor immunity.ConclusionIn this pilot study, we identified several significantly differentially abundant metabolites according to body composition phenotypes, confirming that clinically significant joint-exposure body composition phenotypes are also biologically distinct. Although we observed evidence that at-risk phenotypes were associated with increased abundance of immuno-metabolic biomarkers indicated in immune suppression, additional confirmatory studies focused on defining the link between body composition and immune cell composition and spatial relationships in the EOC tumor microenvironment are warranted.

Serum Anti-PDLIM1 Autoantibody as Diagnostic Marker in Ovarian Cancer

BackgroundSerum autoantibodies (AAbs) against tumor-associated antigens (TAAs) could be useful biomarkers for cancer detection. This study aims to evaluate the diagnostic value of autoantibody against PDLIM1 for improving the detection of ovarian cancer (OC).MethodsImmunohistochemistry (IHC) test in tissue array containing 280 OC tissues, 20 adjacent tissues, and 8 normal ovarian tissues was performed to analyze the expression of PDLIM1 in tissues. Enzyme-linked immunosorbent assay (ELISA) was employed to measure the autoantibody to PDLIM1 in 545 sera samples from 182 patients with OC, 181 patients with ovarian benign diseases, and 182 healthy controls.ResultsThe results of IHC indicated that 84.3% (236/280) OC tissues were positively stained with PDLIM1, while no positive staining was found in adjacent or normal ovarian tissues. The frequency of anti-PDLIM1 autoantibody was significantly higher in OC patients than that in healthy and ovarian benign controls in both training (n=122) and validation (n=423) sets. The area under the curves (AUCs) of anti-PDLIM1 autoantibody for discriminating OC from healthy controls were 0.765 in training set and 0.740 in validation set, and the AUC of anti-PDLIM1 autoantibody for discriminating OC from ovarian benign controls was 0.757 in validation set. Overall, it was able to distinguish 35.7% of OC, 40.6% of patients with early-stage, and 39.5% of patients with late-stage. When combined with CA125, the AUC increased to 0.846, and 79.2% of OC were detected, which is statistically higher than CA125 (61.7%) or anti-PDLIM1(35.7%) alone (p<0.001). Also, anti-PDLIM1 autoantibody could identify 15% (18/120) of patients that were negative with CA125 (CA125 <35 U/ml).ConclusionsThe anti-PDLIM1 autoantibody response in OC patients was positively correlated with PDLIM1 high expression in OC tissues, suggesting that the autoantibody against PDLIM1 might have the potential to be a novel serological biomarker of OC, serving as a complementary measure of CA125, which could improve the power of OC detection.

BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages

High-grade serous ovarian cancer (HGSOC), with its high recurrence rates, urges for reasonable therapeutic strategies that can prolong overall survival. A tumor microenvironment (TME) discloses prognostic and prospective information on cancer, such as the expression level of PD-1 or PD-L1. However, in HGSOC, the impact of the therapies aiming at these targets remains unsatisfying. Tumor-associated macrophages (TAMs) in HGSOC make up a large part of the TMEs and transform between diverse phenotypes under different treatments. AZD5153 inhibiting BRD4, as a potential therapeutic strategy for HGSOC, was demonstrated to confer controversial plasticity on TAMs, which shows the need to uncover its impact on TAMs in HGSOC. Therefore, we established models for TAMs and TAMs co-culturing with T lymphocytes

Expansion of Human Papillomavirus-Specific T Cells in Periphery and Cervix in a Therapeutic Vaccine Recipient Whose Cervical High-Grade Squamous Intraepithelial Lesion Regressed

Advances in high-throughput sequencing have revolutionized the manner with which we can study T cell responses. We describe a woman who received a human papillomavirus (HPV) therapeutic vaccine called PepCan, and experienced complete resolution of her cervical high-grade squamous intraepithelial lesion. By performing bulk T cell receptor (TCR) β deep sequencing of peripheral blood mononuclear cells before and after 4 vaccinations, 70 putatively vaccine-specific clonotypes were identified for being significantly increased using a beta-binomial model. In order to verify the vaccine-specificity of these clonotypes, T cells with specificity to a region, HPV 16 E6 91-115, previously identified to be vaccine-induced using an interferon-γ enzyme-linked immunospot assay, were sorted and analyzed using single-cell RNA-seq and TCR sequencing. HPV specificity in 60 of the 70 clonotypes identified to be vaccine-specific was demonstrated. TCR β bulk sequencing of the cervical liquid-based cytology samples and cervical formalin-fixed paraffin-embedded samples before and after 4 vaccinations demonstrated the presence of these HPV-specific T cells in the cervix. Combining traditional and cutting-edge immunomonitoring techniques enabled us to demonstrate expansion of HPV-antigen specific T cells not only in the periphery but also in the cervix. Such an approach should be useful as a novel approach to assess vaccine-specific responses in various anatomical areas.

Immune checkpoint inhibitor outcomes and prognostic factors in gynecologic tract melanoma: a single-center analysis

IntroductionGynecologic tract melanoma (GTM) is a rare and aggressive malignancy with limited treatment options and poor prognosis. This study aims to evaluate the outcomes of immune checkpoint inhibitors (ICIs) in patients with GTM and identify prognostic factors influencing survival.MethodsA retrospective analysis was conducted on 45 patients diagnosed with GTM at West China Second University Hospital from January 2019 to September 2024. Data on demographics, clinical characteristics, treatments, and outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and Cox proportional-hazards models.ResultsAmong 45 patients, 24 had vaginal melanoma, 18 had vulvar melanoma, and 3 had cervical melanoma. ICIs were administered to 21 patients, but no significant survival benefit was observed. The 1-, 3-, and 5-year survival rates were 87%, 63%, and 31%, respectively. Univariate analysis revealed that patients with a family history of cancer (FHC) and those with lactate dehydrogenase (LDH) levels ≤230 had better PFS. Additionally, FHC, American Joint Committee on Cancer (AJCC) stage I-II, absence of pelvic lymph node metastasis, and LDH levels ≤230 were associated with improved OS. However, in multivariate analysis, only LDH was significantly associated with OS.ConclusionThis single-center study suggests that ICIs have limited efficacy in treating GTM, emphasizing the need for further investigation through larger, multicenter clinical trials. Prognostic factors such as FHC, AJCC stage, lymph node involvement, and LDH levels may aid in risk stratification and personalized treatment planning. However, due to the nature of this study, external cohorts are still needed for validation.

Immunomodulatory role of RNA modifications in sex hormone-dependent cancers

Recent studies have identified that RNA epigenetic modifications, including m6A, m1A, m5C, etc, play pivotal roles in tumor progression. These modifications influence mRNA stability, RNA processing, translational efficiency, and decoding precision. However, comprehensive reviews detailing the connection between m6A RNA modifications and hormone-dependent cancers in both male and female populations remain scarce(breast cancer, ovarian cancer, and endometrial cancer, prostate cancer). In this article, we explore the cellular and molecular roles of various RNA modifications alongside the key elements of the tumor microenvironment. We examine how these RNA modifications influence the development of hormone-dependent cancers through their impact on immune mechanisms. By enhancing our understanding of the function of RNA modifications within the immune systems of four specific tumors, we offer fresh insights for their potential applications in diagnosis and treatment.

Significance of CD47 and Its Association With Tumor Immune Microenvironment Heterogeneity in Ovarian Cancer

BackgroundIt was reported that tumor heterogeneity and the surrounding tumor microenvironment (TME) in ovarian cancer affects immunotherapy efficacy and patient outcomes. And the TME of ovarian cancer is intrinsically heterogeneous. CD47 plays vital roles in cell functional behavior and immune homeostasis relating to cancer prognosis. But how it affects TME and its contribution to heterogeneity in ovarian cancer has not been fully illustrated. Therefore, we aimed to identify a prognostic biomarker which may help explain tumor immune microenvironment heterogeneity of ovarian cancer.MethodsCancer single-cell state atlas (CancerSEA) was used to evaluate functional role of CD47. Several bioinformatics database including Oncomine, Gene Expression Profiling Interaction Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), The Human Protein Atlas (HPA), Ualcan and Kaplan-Meier plotter (KM plotter) were applied to illustrate correlation of CD47 with ovarian cancer prognosis and immune infiltration. Tumor Immune Single-cell Hub (TISCH) single cell database was employed to evaluate correlation of CD47 with tumor microenvironment. GeneMANIA was implemented to identify regulation networks of CD47. Differentially expressed genes (DEGs) between CD47 high and low expression groups were analyzed with R package DESeq2. Kyoto encyclopedia of genes and genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were utilized to explore how CD47 affect the immune related cell signaling pathway.ResultsCD47 expression was upregulated and connected to worse OS and PFS in ovarian cancer. Close relation was found between CD47 expression level and immune infiltration in ovarian cancer, especially with Treg cells, Monocytes, Macrophages and T cell exhaustion (P<0.05). The CD47 expression level was relatively low in plasma cells, dendritic cells and Mono/Macro cells of OV_GSE115007, in myofibroblasts, fibroblasts and endothelial cells of OV_GSE118828, compared to malignant cells of OV_GSE118828 dataset. The cell components and distribution in primary and metastatic ovarian cancer are quite distinct, which may lead to TME heterogeneity of ovarian cancer.ConclusionOur results indicated that CD47 is closely correlated to ovarian cancer immune microenvironment and might induce ovarian cancer heterogeneity. Therefore, CD47 may be used as a candidate prognostic biomarker and provide us with new insights into potential immunotherapy in ovarian cancer patients.

The Immunological Role of CDK4/6 and Potential Mechanism Exploration in Ovarian Cancer

BackgroundOvarian cancer (OC) is one of the most lethal gynecologic cancers. Growing evidence has proven that CDK4/6 plays a key role in tumor immunity and the prognosis of many cancers. However, the expression and function of CDK4/6 in OC remain unclear. Therefore, we aimed to explore the influence of CDK4/6 in OC, especially on immunity.MethodsWe analyzed CDK4/6 expression and prognosis using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Genotype Tissue Expression (GTEx) data. Subsequently, we used the cytoHubba plug-in of Cytoscape software and starBase to identify the noncoding RNAs (ncRNAs) regulating CDK4/6. Finally, we verified the effect of CDK4/6 on immunity in OC cell lines and animal models.ResultsCDK4/6 expression was higher in OC tissues than in normal ovarian tissues, and the high expression levels of CDK4/6 contributed to the immunosuppressive state of OC and were thus related to the poor prognosis of OC patients. This was also in general agreement with the results of OC cell line and animal experiments. Mechanistically, the CDK4/6 inhibitor palbociclib increased the secretion of interferon (IFN)-γ and the interferon-stimulated gene (ISG) response, thereby upregulating the expression of antigen-presenting molecules; this effect was partly dependent on the STING pathway and thus activated immunity in OC. Additionally, according to public data, the LRRC75A-AS1-hsa-miR-330-5p axis could inhibit the immune response of OC patients by upregulating CDK4/6, leading to a poor prognosis.ConclusionCDK4/6 affects the immune microenvironment of OC and correlates with the prognosis of OC patients.

Multi-Omics Profiling Identifies Risk Hypoxia-Related Signatures for Ovarian Cancer Prognosis

BackgroundOvarian cancer (OC) has the highest mortality rate among gynecologic malignancy. Hypoxia is a driver of the malignant progression in OC, which results in poor prognosis. We herein aimed to develop a validated model that was based on the hypoxia genes to systematically evaluate its prognosis in tumor immune microenvironment (TIM).ResultsWe identified 395 hypoxia-immune genes using weighted gene co-expression network analysis (WGCNA). We then established a nine hypoxia-related genes risk model using least absolute shrinkage and selection operator (LASSO) Cox regression, which efficiently distinguished high-risk patients from low-risk ones. We found that high-risk patients were significantly related to poor prognosis. The high-risk group showed unique immunosuppressive microenvironment, lower antigen presentation, and higher levels of inhibitory cytokines. There were also significant differences in somatic copy number alterations (SCNAs) and mutations between the high- and low-risk groups, indicating immune escape in the high-risk group. Tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms showed that low-risk patients are significantly responsive to programmed cell death protein-1 (PD-1) inhibitors.ConclusionsIn this study, we highlighted the clinical significance of hypoxia in OC and established a hypoxia-related model for predicting prognosis and providing potential immunotherapy strategies.

Identification and Validation of Immune-Related Gene for Predicting Prognosis and Therapeutic Response in Ovarian Cancer

Ovarian cancer (OC) is a devastating malignancy with a poor prognosis. The complex tumor immune microenvironment results in only a small number of patients benefiting from immunotherapy. To explore the different factors that lead to immune invasion and determine prognosis and response to immune checkpoint inhibitors (ICIs), we established a prognostic risk scoring model (PRSM) with differential expression of immune-related genes (IRGs) to identify key prognostic IRGs. Patients were divided into high-risk and low-risk groups according to their immune and stromal scores. We used a bioinformatics method to identify four key IRGs that had differences in expression between the two groups and affected prognosis. We evaluated the sensitivity of treatment from three aspects, namely chemotherapy, targeted inhibitors (TIs), and immunotherapy, to evaluate the value of prediction models and key prognostic IRGs in the clinical treatment of OC. Univariate and multivariate Cox regression analyses revealed that these four key IRGs were independent prognostic factors of overall survival in OC patients. In the high-risk group comprising four genes, macrophage M0 cells, macrophage M2 cells, and regulatory T cells, observed to be associated with poor overall survival in our study, were higher. The high-risk group had a high immunophenoscore, indicating a better response to ICIs. Taken together, we constructed a PRSM and identified four key prognostic IRGs for predicting survival and response to ICIs. Finally, the expression of these key genes in OC was evaluated using RT-qPCR. Thus, these genes provide a novel predictive biomarker for immunotherapy and immunomodulation.

Therapeutic strategies targeting folate receptor α for ovarian cancer

Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer, and presents a major clinical challenge due to limited treatment options. Folate receptor alpha (FRα), encoded by the FOLR1 gene, is an attractive therapeutically target due to its prevalent and high expression in EOC cells. Recent basic and translational studies have explored several modalities, such as antibody-drug conjugate (ADC), monoclonal antibodies, small molecules, and folate-drug conjugate, to exploit FRα for EOC treatment. In this review, we summarize the function of FRα, and clinical efficacies of various FRα-based therapeutics. We highlight mirvetuximab soravtansine (MIRV), or Elahere (ImmunoGen), the first FRα-targeting ADC approved by the FDA to treat platinum-resistant ovarian cancer. We discuss potential mechanisms and management of ocular adverse events associated with MIRV administration.

Comprehensive of N1-Methyladenosine Modifications Patterns and Immunological Characteristics in Ovarian Cancer

Backgroundrecently, many researches have concentrated on the relevance between N1-methyladenosine (m1A) methylation modifications and tumor progression and prognosis. However, it remains unknown whether m1A modification has an effect in the prognosis of ovarian cancer (OC) and its immune infiltration.MethodsBased on 10 m1A modulators, we comprehensively assessed m1A modification patterns in 474 OC patients and linked them to TME immune infiltration characteristics. m1Ascore computed with principal component analysis algorithm was applied to quantify m1A modification pattern in OC patients. m1A regulators protein and mRNA expression were respectively obtained by HPA website and RT-PCR in clinical OC and normal samples.ResultsWe finally identified three different m1A modification patterns. The immune infiltration features of these m1A modification patterns correspond to three tumor immune phenotypes, including immune-desert, immune-inflamed and immune-excluded phenotypes. The results demonstrate individual tumor m1A modification patterns can predict patient survival, stage and grade. The m1Ascore was calculated to quantify individual OC patient’s m1A modification pattern. A high m1Ascore is usually accompanied by a better survival advantage and a lower mutational load. Research on m1Ascore in the treatment of OC patients showed that patients with high m1Ascore showed marked therapeutic benefits and clinical outcomes in terms of chemotherapy and immunotherapy. Lastly, we obtained four small molecule drugs that may potentially ameliorate prognosis.ConclusionThis research demonstrates that m1A methylation modification makes an essential function in the prognosis of OC and in shaping the immune microenvironment. Comprehensive evaluation of m1A modifications improves our knowledge of immune infiltration profile and provides a more efficient individualized immunotherapy strategy for OC patients.

Construction of an Immune Cell Infiltration Score to Evaluate the Prognosis and Therapeutic Efficacy of Ovarian Cancer Patients

BackgroundOvarian cancer (OC) is an immunogenetic disease that contains tumor-infiltrating lymphocytes (TILs), and immunotherapy has become a novel treatment for OC. With the development of next-generation sequencing (NGS), profiles of gene expression and comprehensive landscape of immune cells can be applied to predict clinical outcome and response to immunotherapy.MethodsWe obtained data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and applied two computational algorithms (CIBERSORT and ESTIMATE) for consensus clustering of immune cells. Patients were divided into two subtypes using immune cell infiltration (ICI) levels. Then, differentially expressed genes (DEGs) associated with immune cell infiltration (ICI) level were identified. We also constructed ICI score after principle-component analysis (PCA) for dimension reduction.ResultsPatients in ICI cluster B had better survival than those in ICI cluster A. After construction of ICI score, we found that high ICI score had better clinical OS and significantly higher tumor mutation burden (TMB). According to the expression of immune checkpoints, the results showed that patients in high ICI group showed high expression of CTLA4, PD1, PD-L1, and PD-L2, which implies that they might benefit from immunotherapy. Besides, patients in high ICI group showed higher sensitivity to two first-line chemotherapy drugs (Paclitaxel and Cisplatin).ConclusionICI score is an effective prognosis-related biomarker for OC and can provide valuable information on the potential response to immunotherapy.

Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence

Immune checkpoint blockade (ICB) relieves CD8+T-cell exhaustion in most mutated tumors, and TCF-1 is implicated in converting progenitor exhausted cells to functional effector cells. However, identifying mechanisms that can prevent functional senescence and potentiate CD8+T-cell persistence for ICB non-responsive and resistant tumors remains elusive. We demonstrate that targetingCbx3/HP1γ in CD8+T cells augments transcription initiation and chromatin remodeling leading to increased transcriptional activity atLef1andIl21r. LEF-1 and IL-21R are necessary forCbx3/HP1γ-deficient CD8+effector T cells to persist and control ovarian cancer, melanoma, and neuroblastoma in preclinical models. The enhanced persistence ofCbx3/HP1γ-deficient CD8+T cells facilitates remodeling of the tumor chemokine/receptor landscape ensuring their optimal invasion at the expense of CD4+Tregs. Thus, CD8+T cells heightened effector function consequent toCbx3/HP1γ deficiency may be distinct from functional reactivation by ICB, implicatingCbx3/HP1γ as a viable cancer T-cell-based therapy target for ICB resistant, non-responsive solid tumors.

Comprehensive Analyses Identify APOBEC3A as a Genomic Instability-Associated Immune Prognostic Biomarker in Ovarian Cancer

Ovarian cancer (OC) is one of the most malignant tumors whose mortality rate ranks first in gynecological tumors. Although immunotherapy sheds new light on clinical treatments, the low response still restricts its clinical use because of the unique characteristics of OC such as immunosuppressive microenvironment and unstable genomes. Further exploration on determining an efficient biomarker to predict the immunotherapy response of OC patients is of vital importance. In this study, integrative analyses were performed systematically using transcriptome profiles and somatic mutation data from The Cancer Genome Atlas (TCGA) based on the immune microenvironment and genomic instability of OC patients. Firstly, intersection analysis was conducted to identify immune-related differentially expressed genes (DEGs) and genomic instability-related DEGs. Secondly, Apolipoprotein B MRNA Editing Enzyme Catalytic Subunit 3A (APOBEC3A) was recognized as a protective factor for OC, which was also verified through basic experiments such as quantitative reverse transcription PCR (RT-qPCR), immunohistochemistry (IHC), Cell Counting Kit-8 (CCK-8), and transwell assays. Thirdly, the correlation analyses of APOBEC3A expression with tumor-infiltrating immune cells (TICs), inhibitory checkpoint molecules (ICPs), Immunophenoscores (IPS), and response to anti-PD-L1 immunotherapy were further applied along with single-sample GSEA (ssGSEA), demonstrating APOBEC3A as a promising biomarker to forecast the immunotherapy response of OC patients. Last, the relationship between APOBEC3A expression with tumor mutation burden (TMB), DNA damage response (DDR) genes, and m6A-related regulators was also analyzed along with the experimental verification of immunofluorescence (IF) and RT-qPCR, comprehensively confirming the intimate association of APOBEC3A with genomic instability in OC. In conclusion, APOBEC3A was identified as a protective signature and a promising prognostic biomarker for forecasting the survival and immunotherapy effect of OC patients, which might accelerate the clinical application and improve immunotherapy effect.

Targeting DNA Repair Response Promotes Immunotherapy in Ovarian Cancer: Rationale and Clinical Application

Immune checkpoint inhibitors (ICI) have emerged as a powerful oncologic treatment modality for patients with different solid tumors. Unfortunately, the efficacy of ICI monotherapy in ovarian cancer is limited, and combination therapy provides a new opportunity for immunotherapy in ovarian cancer. DNA damage repair (DDR) pathways play central roles in the maintenance of genomic integrity and promote the progression of cancer. A deficiency in DDR genes can cause different degrees of DNA damage that enhance local antigen release, resulting in systemic antitumor immune responses. Thus, the combination of DDR inhibitors with ICI represents an attractive therapeutic strategy with the potential to improve the clinical outcomes of patients with ovarian cancer. In this review, we provide an overview of the interconnectivity between DDR pathway deficiency and immune response, summarize available clinical trials on the combination therapy in ovarian cancer, and discuss the potential predictive biomarkers that can be utilized to guide the use of combination therapy.

Infiltration by CXCL10 Secreting Macrophages Is Associated With Antitumor Immunity and Response to Therapy in Ovarian Cancer Subtypes

Ovarian carcinomas (OCs) are poorly immunogenic and immune checkpoint inhibitors (ICIs) have offered a modest benefit. In this study, high CD3+ T-cells and CD163+ tumor-associated macrophages (TAMs) densities identify a subgroup of immune infiltrated high-grade serous carcinomas (HGSCs) with better outcomes and superior response to platinum-based therapies. On the contrary, in most clear cell carcinomas (CCCs) showing poor prognosis and refractory to platinum, a high TAM density is associated with low T cell frequency. Immune infiltrated HGSC are characterized by the 30-genes signature (OC-IS30) covering immune activation and IFNγ polarization and predicting good prognosis (n = 312, TCGA). Immune infiltrated HGSC contain CXCL10 producing M1-type TAM (IRF1+pSTAT1Y701+) in close proximity to T-cells. A fraction of these M1-type TAM also co-expresses TREM2. M1-polarized TAM were barely detectable in T-cell poor CCC, but identifiable across various immunogenic human cancers. Single cell RNA sequencing data confirm the existence of a tumor-infiltrating CXCL10+IRF1+STAT1+ M1-type TAM overexpressing antigen processing and presentation gene programs. Overall, this study highlights the clinical relevance of the CXCL10+IRF1+STAT1+ macrophage subset as biomarker for intratumoral T-cell activation and therefore offers a new tool to select patients more likely to respond to T-cell or macrophage-targeted immunotherapies.

Shaping Immune Responses in the Tumor Microenvironment of Ovarian Cancer

Reciprocal signaling between immune cells and ovarian cancer cells in the tumor microenvironment can alter immune responses and regulate disease progression. These signaling events are regulated by multiple factors, including genetic and epigenetic alterations in both the ovarian cancer cells and immune cells, as well as cytokine pathways. Multiple immune cell types are recruited to the ovarian cancer tumor microenvironment, and new insights about the complexity of their interactions have emerged in recent years. The growing understanding of immune cell function in the ovarian cancer tumor microenvironment has important implications for biomarker discovery and therapeutic development. This review aims to describe the factors that shape the phenotypes of immune cells in the tumor microenvironment of ovarian cancer and how these changes impact disease progression and therapy.

T-Cell Receptor Therapy in the Treatment of Ovarian Cancer: A Mini Review

Ovarian cancer, in particularly high-grade serous ovarian cancer (HGSOC) and ovarian carcinosarcoma (OCS), are highly aggressive and deadly female cancers with limited treatment options. These tumors are generally unresponsive to immune check-point inhibitor (ICI) therapy and are referred to as immunologically “cold” tumors. Cell-based therapy, in particular, adoptive T-cell therapy, is an alternative immunotherapy option that has shown great potential, especially chimeric antigen receptor T cell (CAR-T) therapy in the treatment of hematologic malignancies. However, the efficacy of CAR-T therapy in solid tumors has been modest. This review explores the potential of another cell-based therapy, T-cell receptor therapy (TCR-T) as an alternate treatment option for immunological “cold” OC and OCS tumors.

Bispecific T-Cell Engaging Antibodies Against MUC16 Demonstrate Efficacy Against Ovarian Cancer in Monotherapy and in Combination With PD-1 and VEGF Inhibition

Immunotherapy for ovarian cancer is an area of intense investigation since the majority of women with relapsed disease develop resistance to conventional cytotoxic therapy. The paucity of safe and validated target antigens has limited the development of clinically relevant antibody-based immunotherapeutics for this disease. Although MUC16 expression is almost universal in High Grade Serous Ovarian Cancers, engagement of the shed circulating MUC16 antigen (CA-125) presents a theoretical risk of systemic activation and toxicity. We designed and evaluated a series of bispecific tandem single-chain variable fragments specific to the retained portion of human MUC16 ectodomain (MUC16ecto) and human CD3. These MUC16ecto- BiTEDs retain binding in the presence of soluble MUC16 (CA-125) and show cytotoxicity against a panel of ovarian cancer cells in vitro. MUC16ecto- BiTEDs delay tumor progression in vivo and significantly prolong survival in a xenograft model of ovarian peritoneal carcinomatosis. This effect was significantly enhanced by antiangiogenic (anti-VEGF) therapy and immune checkpoint inhibition (anti-PD1). However, the combination of BiTEDs with anti-VEGF was superior to combination with anti-PD1, based on findings of decreased peritoneal tumor burden and ascites with the former. This study shows the feasibility and efficacy of MUC16ecto- specific BiTEDs and provides a basis for the combination with anti-VEGF therapy for ovarian cancer.

Double Insurance for OC: miRNA-Mediated Platinum Resistance and Immune Escape

Ovarian cancer (OC) is still the leading cause of death among all gynecological malignancies, despite the recent progress in cancer therapy. Immune escape and drug resistance, especially platinum-based chemotherapy, are significant factors causing disease progression, recurrence and poor prognosis in OC patients. MicroRNAs(miRNAs) are small noncoding RNAs, regulating gene expression at the transcriptional level. Accumulating evidence have indicated their crucial roles in platinum resistance. Importantly, they also act as mediators of tumor immune escape/evasion. In this review, we summarize the recent study of miRNAs involved in platinum resistance of OC and systematically analyses miRNAs involved in the regulation of OC immune escape. Further understanding of miRNAs roles and their possible mechanisms in platinum resistance and tumor escape may open new avenues for improving OC therapy.

Modulating the tumor immune microenvironment with nanoparticles: A sword for improving the efficiency of ovarian cancer immunotherapy

With encouraging antitumor effects, immunotherapy represented by immune checkpoint blockade has developed into a mainstream cancer therapeutic modality. However, only a minority of ovarian cancer (OC) patients could benefit from immunotherapy. The main reason is that most OC harbor a suppressive tumor immune microenvironment (TIME). Emerging studies suggest that M2 tumor-associated macrophages (TAMs), T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs) are enriched in OC. Thus, reversing the suppressive TIME is considered an ideal candidate for improving the efficiency of immunotherapy. Nanoparticles encapsulating immunoregulatory agents can regulate immunocytes and improve the TIME to boost the antitumor immune response. In addition, some nanoparticle-mediated photodynamic and photothermal therapy can directly kill tumor cells and induce tumor immunogenic cell death to activate antigen-presenting cells and promote T cell infiltration. These advantages make nanoparticles promising candidates for modulating the TIME and improving OC immunotherapy. In this review, we analyzed the composition and function of the TIME in OC and summarized the current clinical progress of OC immunotherapy. Then, we expounded on the promising advances in nanomaterial-mediated immunotherapy for modulating the TIME in OC. Finally, we discussed the obstacles and challenges in the clinical translation of this novel combination treatment regimen. We believe this resourceful strategy will open the door to effective immunotherapy of OC and benefit numerous patients.

Integration of local and systemic immunity in ovarian cancer: Implications for immunotherapy

Cancer is a disease that induces many local and systemic changes in immunity. The difficult nature of ovarian cancer stems from the lack of characteristic symptoms that contributes to a delayed diagnosis and treatment. Despite the enormous progress in immunotherapy, its efficacy remains limited. The heterogeneity of tumors, lack of diagnostic biomarkers, and complex immune landscape are the main challenges in the treatment of ovarian cancer. Integrative approaches that combine the tumor microenvironment – local immunity – together with periphery – systemic immunity – are urgently needed to improve the understanding of the disease and the efficacy of treatment. In fact, multiparametric analyses are poised to improve our understanding of ovarian tumor immunology. We outline an integrative approach including local and systemic immunity in ovarian cancer. Understanding the nature of both localized and systemic immune responses will be crucial to boosting the efficacy of immunotherapies in ovarian cancer patients.

Elevation of circulating TNF receptor 2 in cancer: A systematic meta-analysis for its potential as a diagnostic cancer biomarker

High Tumor Necrosis Factor Receptor 2 (TNFR2) expression is characteristic of diverse malignant cells during tumorigenesis. The protein is also expressed by many immunosuppressive cells during cancer development, allowing cancer immune escape. A growing body of evidence further suggests a correlation between the circulating form of this protein and cancer development. Here we conducted a systematic meta-analysis of cancer studies published up until 1stOctober 2022, in which the circulating soluble TNFR2 (sTNFR2) concentrations in patients with cancers were recorded and their association with cancer risk was assessed. Of the 14,615 identified articles, 44 studies provided data on the correlation between cancer risk and the level of circulating sTNFR2. The pooled means comparison showed a consistently significant increase in the levels of sTNFR2 in diverse cancers when compared to healthy controls. These included colorectal cancer, ovarian cancer, breast cancer, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, lung cancer, hepatocarcinoma, and glioblastoma. In a random-effect meta-analysis, the cancer-specific odd ratios (OR) showed significant correlations between increased circulating sTNFR2 levels and the risk of colorectal cancer, non-Hodgkin’s lymphoma, and hepatocarcinoma at 1.59 (95% CI:1.20-2.11), 1.98 (95% CI:1.49-2.64) and 4.32 (95% CI:2.25-8.31) respectively. The overall result showed an association between circulating levels of sTNFR2 and the risk of developing cancer at 1.76 (95% CI:1.53-2.02). This meta-analysis supports sTNFR2 as a potential diagnostic biomarker for cancer, albeit with different predictive strengths for different cancer types. This is consistent with a potential key role for TNFR2 involvement in cancer development.

Research progress on anti-ovarian cancer mechanism of miRNA regulating tumor microenvironment

Ovarian cancer is the most deadly malignancy among women, but its complex pathogenesis is unknown. Most patients with ovarian cancer have a poor prognosis due to high recurrence rates and chemotherapy resistance as well as the lack of effective early diagnostic methods. The tumor microenvironment mainly includes extracellular matrix, CAFs, tumor angiogenesis and immune-associated cells. The interaction between tumor cells and TME plays a key role in tumorigenesis, progression, metastasis and treatment, affecting tumor progression. Therefore, it is significant to find new tumor biomarkers and therapeutic targets. MicroRNAs are non-coding RNAs that post-transcriptionally regulate the expression of target genes and affect a variety of biological processes. Studies have shown that miRNAs regulate tumor development by affecting TME. In this review, we summarize the mechanisms by which miRNAs affect ovarian cancer by regulating TME and highlight the key role of miRNAs in TME, which provides new targets and theoretical basis for ovarian cancer treatment.

Case report: Local cryoablation combined with pembrolizumab to eliminate lung metastases from ovarian clear cell carcinoma

Ovarian clear cell carcinoma has a high recurrence rate with poor prognosis and is generally not sensitive to conventional platinum-based chemotherapy. Its less frequent occurrence of mutations such as BRCA limited the targeted therapies. Immunotherapy is not currently recommended as a first-line agent for ovarian cancer, and most patients are not yet able to benefit from it. Cryoablation can be used to treat solid systemic tumors, including ovarian cancer metastases, and can produce a limited anti-tumor immune response. The anti-tumor effects of cryoablation combined with immunotherapy have not been adequately confirmed. This study reports a case of a patient with ovarian clear cell carcinoma who underwent conventional adjuvant chemotherapy after initially surgical resection of the tumor. Unfortunately, cancer recurred and metastasized to the abdominal wall. After a series of painful chemotherapy and a second surgery, the cancer was still not effectively controlled, and the patient developed extensive metastases in the lung. The patient’s PD-L1 expression level also did not support solo immunotherapy. We pioneered the use of cryoablation to first eradicate the most significant lesion in the upper lobe of the left lung and then combined it with the PD-L1 inhibitor pembrolizumab to treat the patient with immunotherapy, which resulted in the complete eradication of the other multiple metastases in the lung and saved the patient’s life. Although the precise mechanism of action has not yet been explored, we have reason to believe that the combination of cryoablation and immune checkpoint inhibitor has a powerful synergistic anti-tumor effect, which is yet to be confirmed by more basic research and clinical applications in the next step.

Tumor-infiltrating lymphocytes for treatment of solid tumors: It takes two to tango?

Tumor-infiltrating lymphocytes (TILs), frontline soldiers of the adaptive immune system, are recruited into the tumor site to fight against tumors. However, their small number and reduced activity limit their ability to overcome the tumor. Enhancement of TILs number and activity against tumors has been of interest for a long time. A lack of knowledge about the tumor microenvironment (TME) has limited success in primary TIL therapies. Although the advent of engineered T cells has revolutionized the immunotherapy methods of hematologic cancers, the heterogeneity of solid tumors warrants the application of TILs with a wide range of specificity. Recent advances in understanding TME, immune exhaustion, and immune checkpoints have paved the way for TIL therapy regimens. Nowadays, TIL therapy has regained attention as a safe personalized immunotherapy, and currently, several clinical trials are evaluating the efficacy of TIL therapy in patients who have failed conventional immunotherapies. Gaining favorable outcomes following TIL therapy of patients with metastatic melanoma, cervical cancer, ovarian cancer, and breast cancer has raised hope in patients with refractory solid tumors, too. Nevertheless, TIL therapy procedures face several challenges, such as high cost, timely expansion, and technical challenges in selecting and activating the cells. Herein, we reviewed the recent advances in the TIL therapy of solid tumors and discussed the challenges and perspectives.

The current landscape of predictive and prognostic biomarkers for immune checkpoint blockade in ovarian cancer

Immune checkpoint blockade (ICB) therapy has evoked a prominent shift in anticancer therapy. Durable clinical antitumor activity to ICB has been observed in patients with ovarian cancer (OC). However, only a subset of patients derive clinical benefit, and immune-related adverse events (irAEs) caused by ICB therapy can lead to permanent tissue damage and even fatal consequences. It is thus urgent to develop predictive biomarkers to optimize patient outcomes and minimize toxicity risk. Herein, we review current predictive and prognostic biomarkers for checkpoint immunotherapy in OC and highlight emerging biomarkers to guide treatment with ICB. The prevalent biomarkers, such as PD-L1 expression status, tumor-infiltrating lymphocytes, mutational burden, and immune gene signatures, are further discussed. We provide a state-of-the-art survey on prognostic and predictive biomarkers for checkpoint immunotherapy and offer valuable information for guiding precision immunotherapy

Metabolic reprogramming of the tumor immune microenvironment in ovarian cancer: A novel orientation for immunotherapy

Ovarian cancer is the most lethal gynecologic tumor, with the highest mortality rate. Numerous studies have been conducted on the treatment of ovarian cancer in the hopes of improving therapeutic outcomes. Immune cells have been revealed to play a dual function in the development of ovarian cancer, acting as both tumor promoters and tumor suppressors. Increasingly, the tumor immune microenvironment (TIME) has been proposed and confirmed to play a unique role in tumor development and treatment by altering immunosuppressive and cytotoxic responses in the vicinity of tumor cells through metabolic reprogramming. Furthermore, studies of immunometabolism have provided new insights into the understanding of the TIME. Targeting or activating metabolic processes of the TIME has the potential to be an antitumor therapy modality. In this review, we summarize the composition of the TIME of ovarian cancer and its metabolic reprogramming, its relationship with drug resistance in ovarian cancer, and recent research advances in immunotherapy.

Tumor infiltrating CD8/CD103/TIM-3-expressing lymphocytes in epithelial ovarian cancer co-express CXCL13 and associate with improved survival

Reactivation of tumor infiltrating T lymphocytes (TILs) with immune checkpoint inhibitors or co-stimulators has proven to be an effective anti-cancer strategy for a broad range of malignancies. However, epithelial ovarian cancer (EOC) remains largely refractory to current T cell-targeting immunotherapeutics. Therefore, identification of novel immune checkpoint targets and biomarkers with prognostic value for EOC is warranted. Combining multicolor immunofluorescent staining’s with single cell RNA-sequencing analysis, we here identified a TIM-3/CXCL13-positive tissue-resident memory (CD8/CD103-positive) T cell (Trm) population in EOC. Analysis of a cohort of ~175 patients with high-grade serous EOC revealed TIM-3-positive Trm were significantly associated with improved patient survival. As CXCL13-positive CD8-positive T cells have been strongly linked to patient response to anti-PD1 immune checkpoint blockade, combinatorial TIM-3 and PD-1 blockade therapy may be of interest for the (re)activation of anti-cancer immunity in EOC.

The role of cancer-associated mesothelial cells in the progression and therapy of ovarian cancer

Ovarian cancer is currently one of the most common malignant tumors in females with poor survival rates around the world, killing about 200,000 women each year. Although great progress has been made in treatment, most patients receiving first-line therapy experience tumor recurrence. The tumor microenvironment plays an important role in regulating the progression and prognosis of ovarian cancer. Cancer-associated mesothelial cells are the main cell population in the tumor microenvironment, which affect the progression, prognosis and chemical resistance of ovarian cancer. Cancer-associated mesothelial cells can also interact with other microenvironmental components, such as exosomes, macrophages, and adipocytes. Some studies have developed drugs targeting cancer-associated mesothelial cells in ovarian cancer to evaluate the therapeutic efficiency. In this review we highlighted the key role of cancer-associated mesothelial cells in the progression and prognosis of ovarian cancer. We also described the progress of cancer-associated mesothelial cells targeted therapy for ovarian cancer. Continued insight into the role of cancer-associated mesothelial cells in ovarian cancer will potentially contribute to the development of new and effective therapeutic regiments.

Development of a Novel Immune Infiltration-Based Gene Signature to Predict Prognosis and Immunotherapy Response of Patients With Cervical Cancer

Predictive models could indicate the clinical outcome of patients with carcinoma. Cervical cancer is one of the most frequently diagnosed female malignancies. Herein, we proposed an immune infiltration-related gene signature that predicts prognosis of patients with cervical cancer and depicts the immune landscape as well. We utilized the transcriptome data of The Cancer Genome Atlas (TCGA) and estimated the infiltration level of 28 immune cell types. We screened out four immune cell types conducive to patient survival and recognized their shared differentially expressed genes (DEGs). Four core genes (CHIT1, GTSF1L, PLA2G2D, and GNG8) that composed the ultimate signature were identified via univariate and multivariate Cox regression. The optimal model we built up could distinguish patients with cervical cancer into high-score and low-score subgroups. These two subgroups showed disparity in aspects of patient survival, immune infiltration landscape, and response to immune checkpoint inhibitors. Additionally, we found that GTSF1L was decreased gradually along with the severity of cervical lesions, and its potential role in immune contexture and clinical practice were also demonstrated. Our results suggested that the Immunoscore based on four immune-related genes could serve as a supplementary criterion to effectively foresee the survival outcome, tumor infiltration status, and immunotherapy efficacy of cervical cancer patients.

Potent Neutralizing Humanized Antibody With Topical Therapeutic Potential Against HPV18-Related Cervical Cancer

Cervical cancer caused by human papillomavirus (HPV) infections is the fourth most common cancer in women worldwide. Current prophylactic HPV vaccines have achieved promising success in preventing HPV infection. However, still 570,000 new cases were reported in 2018. The current primary treatment for the patient with cervical cancer is either surgery or chemoradiotherapy. Cervical cancer still lacks standard medical therapy. HPV18 induced cervical cancer has the worst prognosis and high mortality compared to other HPV infections. The development of HPV18 related with cervical malignancy requires the persistent infection of cervical–vaginal epithelium by HPV18 subtype, which can take years to transform the epithelium. This period of repeated infection provides a window for therapeutic intervention. Neutralizing antibodies formulated as topical agents that inhibit HPV18 infection should reduce the chance of cervical malignancy. We previously demonstrated that potent neutralizing anti-sera against HPV18 infection were induced by HPV18 viral like particle (VLP) generated in mammalian cells. We, therefore, isolated two potent neutralizing antibodies, 2A12 and 8H4, from over 3,810 hybridomas prepared from mice immunized with HPV18 VLP. 2A12 and 8H4 exhibited excellent potency, with 50% virus-inhibitory concentrations (IC50) of 0.4 and 0.9 ng/ml, respectively. Furthermore, 2A12 and 8H4 recognized distinct and non-overlapping quaternary epitopes and bound specifically with HPV18. Humanized 2A12 (Hu2A12) retained comparable neutralizing activity against HPV18 infection in various acidic pH settings and in hydrogel formulation with IC50 values of 0.04 to 0.77 ng/ml, indicating that Hu2A12 will be a promising candidate for clinical development as a topical vaginal biopharmaceutical agent against HPV18 infection.

Multi-Omics Analysis Showed the Clinical Value of Gene Signatures of C1QC+ and SPP1+ TAMs in Cervical Cancer

PurposeTo evaluate the value of C1QC+ and SPP1+ TAMs gene signatures in patients with cervical cancer.MethodsWe compare the C1QC+ and SPP1+ TAMs gene signatures with the M1/M2 gene signatures at single cell level and bulk RNA-seq level and evaluate which gene signature can clearly divide TAMs and patients with cervical cancer into distinct clinical subclusters better.ResultsAt single-cell level, C1QC+ and SPP1+ TAMs gene signatures, but not M1 and M2 gene signatures, could clearly divided TAMs into two subclusters in a colon cancer data set and an advanced basal cell data set. For cervical cancer data from TCGA, patients with C1QChigh and SPP1low TAMs gene signatures have the best prognosis, lowest proportion (34.21%) of locally advanced cervical cancer (LACC), and highest immune cell infiltration, whereas patients with C1QClow and SPP1high TAMs gene signatures have the worst prognosis, highest proportion (71.79%) of LACC and lowest immune cell infiltration. Patients with C1QChigh and SPP1low TAMs gene signature have higher expression of most of the Immune checkpoint molecules (ICMs) than patients with C1QClow and SPP1high TAMs gene signatures. The GSEA results suggested that subgroups of patients divided by C1QC+ and SPP1+ TAMs gene signatures showed different anti- or pro-tumor state.ConclusionC1QC+ and SPP1+ TAMs gene signatures, but not M1/M2 gene signatures, can divide cervical patients into subgroups with different prognosis, tumor stage, different immune cell infiltration, and ICMs expression. Our findings may help to find suitable treatment strategy for cervical cancer patients with different TAMs gene signatures.

Remodeling the tumor microenvironment: regulatory effects of β-sitosterol and luteolin on the immunosuppressive milieu in endometrial carcinoma and implications for combinatorial immunotherapy

Endometrial carcinoma (EC), particularly high-risk molecular subtypes like p53abn and NSMP, is frequently characterized by a tumor immunosuppressive tumor microenvironment (TME) that drives progression, metastasis, and resistance to therapy. This immunosuppressive milieu is orchestrated by key cellular components, including M2-polarized tumor-associated macrophages (TAMs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), PD-L1-expressing tumor cells, and pro-fibrotic cancer-associated fibroblasts (CAFs), which collectively inhibit effector T cell function and promote immune exclusion/desert phenotypes. Natural products offer promising multi-targeted strategies to remodel the TME. This review comprehensively summarizes the potent immunomodulatory effects of the phytosterol β-sitosterol (BSS) and the flavonoid luteolin (Lut) specifically within the EC TME. We detail how BSS and Lut synergistically reprogram TAMs towards an M1 phenotype, inhibit Treg differentiation/function and MDSC expansion, enhance CD8 + T cell recruitment, activation, and cytotoxicity (e.g., by downregulating PD-1/TIM-3), and suppress CAF-mediated immunosuppression and fibrosis. Mechanistically, these effects are achieved through targeting critical signaling pathways (STAT3, NF-κB, PI3K/AKT, Wnt/β-catenin) and modulating key chemokines/cytokines (e.g., reducing TGF-β, IL-10, CXCL12; increasing CXCL9/10, IFN-γ). Critically, BSS and Lut demonstrate significant potential to overcome resistance to immune checkpoint inhibitors (ICIs), particularly in immune-cold EC subtypes. By remodeling the immunosuppressive TME, BSS/Lut combinations can enhance ICI efficacy, as evidenced by preclinical data showing increased tumor suppression rates and T cell infiltration. While challenges remain, including EC-specific validation, bioavailability optimization, and molecular subtype stratification, BSS and Lut represent promising natural adjuvants for combinatorial immunotherapy, offering novel strategies to improve outcomes for patients with aggressive or treatment-refractory EC.

HLA-G 3’UTR polymorphism diplotypes and soluble HLA-G plasma levels impact cervical cancer susceptibility and prognosis

BackgroundHuman leukocyte antigen G (HLA-G) is an immune checkpoint molecule with relevance in several cancers. The aim of this study was to evaluate the potential role of soluble HLA-G (sHLA-G), its genetic polymorphisms and its haplotype structure in the susceptibility and prognosis of primary cervical cancer in a Chinese Han population.MethodsWe investigated sHLA-G plasma levels and 3’ untranslated region (3’UTR) polymorphisms through ELISA and direct DNA sequencing, respectively, in cervical cancer patients (120 cases) and healthy control women (96 cases). The data were analyzed for associations using PowerMarker, Haploview, and GraphPad Prism.ResultsIn this study, 8 polymorphic sites, 16 haplotypes and 23 diplotypes in the HLA-G 3’UTR were identified in our study population. We observed that each pair of 8 polymorphic sites exhibited linkage disequilibrium. The heterozygote CT genotype at position +3422 (rs17875408) was more common in cervical cancer patients than in healthy women (OR=5.285, P<0.05). Haplotypes UTR-1, UTR-3, and UTR-7 accounted for more than 85% of both groups, but no significant difference was found. The frequency of the UTR-1/UTR-3 diplotype in patients was significantly higher than that in controls (P<0.05). In addition, we further observed that HLA-G 3’UTR polymorphisms may influence the sHLA-G plasma level in patients’ peripheral blood, especially 14 bp Ins/Del (rs371194629) and +3142 C/G (rs1063320). A receiver operating characteristic (ROC) curve analysis showed that the sHLA-G level had good diagnostic performance in differentiating patients with cervical cancer from healthy women (AUC>0.7). Among patients, mean sHLA-G levels increased with increasing FIGO stages but were not related to the overall survival time.ConclusionsThe results of the present study enhance our understanding of how HLA-G 3’UTR polymorphisms can influence the peripheral sHLA-G plasma level and play a key role in cervical carcinogenesis. This study further confirmed that sHLA-G may represent a novel plasma biomarker for the prognosis and potential therapeutic target of cervical cancer.

Perspectives of ERCC1 in early-stage and advanced cervical cancer: From experiments to clinical applications

Cervical cancer is a public health problem of extensive clinical importance. Excision repair cross-complementation group 1 (ERCC1) was found to be a promising biomarker of cervical cancer over the years. At present, there is no relevant review article that summarizes such evidence. In this review, nineteen eligible studies were included for evaluation and data extraction. Based on the data from clinical and experimental studies, ERCC1 plays a key role in the progression of carcinoma of the uterine cervix and the therapeutic response of chemoradiotherapy. The majority of the included studies (13/19, 68%) suggested that ERCC1 played a pro-oncogenic role in both early-stage and advanced cervical cancer. High expression of ERCC1 was found to be associated with the poor survival rates of the patients. ERCC1 polymorphism analyses demonstrated that ERCC1 might be a useful tool for predicting the risk of cervical cancer and the treatment-related toxicities. Experimental studies indicated that the biological effects exerted by ERCC1 in cervical cancer might be mediated by its associated genes and affected signaling pathways (i.e., XPF, TUBB3, and. To move towards clinical applications by targeting ERCC1 in cervical cancer, more clinical, in-vitro, and in-vivo investigations are still warranted in the future.

Integrated single-cell transcriptome analysis of the tumor ecosystems underlying cervical cancer metastasis

Cervical cancer (CC) is one of the most frequent female malignancies worldwide. However, the molecular mechanism of lymph node metastasis in CC remains unclear. In this study, we investigated the transcriptome profile of 51,507 single cells from primary tumors, positive lymph nodes (P-LN), and negative lymph nodes (N-LN) using single-cell sequencing. Validation experiments were performed using bulk transcriptomic datasets and immunohistochemical assays. Our results indicated that epithelial cells in metastatic LN were associated with cell- cycle-related signaling pathways, such as E2F targets, and mitotic spindle, and immune response-related signaling pathways, such as allograft rejection, IL2_STAT5_signaling, and inflammatory response. However, epithelial cells in primary tumors exhibited high enrichment of epithelial-mesenchymal translation (EMT), oxidative phosphorylation, and interferon alpha response. Our analysis then indicated that metastasis LN exhibited an early activated tumor microenvironment (TME) characterized by the decrease of naive T cells and an increase of cytotoxicity CD8 T cells, NK cells, FOXP3+ Treg cells compared with normal LN. By comparing the differently expressed gene of macrophages between tumor and metastatic LN, we discovered that C1QA+ MRC1low macrophages were enriched in a tumor, whereas C1QA+ MRC1high macrophages were enriched in metastatic LN. Finally, we demonstrated that cancer-associated fibroblasts (CAFs) in P-LN were associated with immune regulation, while CAFs in tumor underwent EMT. Our findings offered novel insights into the mechanisms of research, diagnosis, and therapy of CC metastasis.

Mining of immunological and prognostic-related biomarker for cervical cancer based on immune cell signatures

BackgroundImmunotherapy has changed the therapeutic landscape of cervical cancer (CC), but has durable anti-tumor activity only in a subset of patients. This study aims to comprehensively analyze the tumor immune microenvironment (TIME) of CC and to mine biomarkers related to immunotherapy and prognosis.MethodsThe Cancer Genome Atlas (TCGA) data was utilized to identify heterogeneous immune subtypes based on survival-related immune cell signatures (ICSs). ICSs prognostic model was constructed by Cox regression analyses, and immunohistochemistry was conducted to verify the gene with the largest weight coefficient in the model. Meanwhile, the tumor immune infiltration landscape was comprehensively characterized by ESTIMATE, CIBERSORT and MCPcounter algorithms. In addition, we also analyzed the differences in immunotherapy-related biomarkers between high and low-risk groups. IMvigor210 and two gynecologic tumor cohorts were used to validate the reliability and scalability of the Risk score.ResultsA total of 291 TCGA-CC samples were divided into two ICSs clusters with significant differences in immune infiltration landscape and prognosis. ICSs prognostic model was constructed based on eight immune-related genes (IRGs), which showed higher overall survival (OS) rate in the low-risk group (P< 0.001). In the total population, time-dependent receiver operating characteristic (ROC) curves displayed area under the curve (AUC) of 0.870, 0.785 and 0.774 at 1-, 3- and 5-years. Immunohistochemical results showed that the expression of the oncogene (FKBP10) was negatively correlated with the degree of differentiation and positively correlated with tumor stage, while the expression of tumor suppressor genes (S1PR4) was the opposite. In addition, the low-risk group had more favorable immune activation phenotype and higher enrichment of immunotherapy-related biomarkers. The Imvigor210 and two gynecologic tumor cohorts validated a better survival advantage and immune efficacy in the low-risk group.ConclusionThis study comprehensively assessed the TIME of CC and constructed an ICSs prognostic model, which provides an effective tool for predicting patient’s prognosis and accurate immunotherapy.

Salvage high intensity focused ultrasound for residual or recurrent cervical cancer after definitive chemoradiotherapy

ObjectiveThe treatment of residual/recurrent cervical cancer within a previously irradiated area is challenging and generally associated with a poor outcome. Local treatments such as salvage surgery and re-irradiation are usually traumatic and have limited efficacy. High intensity focused ultrasound (HIFU) treatment can directly ablate solid tumors without damaging neighboring healthy tissue. However, the HIFU studies for these patients are limited. Experience gained over the course of 10 years with the use of HIFU for the management of residual/recurrent cervical cancer after chemoradiotherapy is reported herein.Methods153 patients with residual/recurrent cervical cancer in a previously irradiated field who received HIFU treatment between 2010 and 2021 were retrospectively analyzed. Adverse effects, survival benefit and factors affecting prognosis were given particular attention.ResultsA total of 36 patients (23.5%) achieved a partial response following HIFU treatment and 107 patients (69.9%) had stable disease. The objective response and disease control rates were 23.5% and 93.5%, respectively. The median progression-free survival (mPFS) and median overall survival (mOS) were 17.0 months and 24.5 months, respectively. Moreover, patients with lesions ≥1.40 cm before HIFU treatment and a shrinkage rate ≥ 30% after treatment had a higher mPFS and mOS, and patients with lesions ≤1.00 cm after HIFU treatment had a higher mPFS (P=<0.05). All the treatment-related adverse events were limited to minor complications, which included skin burns, abdominal pain and vaginal discharge.ConclusionsHIFU treatment is likely a preferred option for cervical cancer patients with residual disease or recurrence following CRT that can safely improve the local control rate and extend survival.

Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells

Attempts to develop a therapeutic vaccine against human papillomavirus (HPV)-induced malignancies have mostly not been clinically successful to date. One reason may be the hypoxic microenvironment present in most tumors, including cervical cancer. Hypoxia dysregulates the levels of human leukocyte antigen (HLA) class I molecules in different tumor entities, impacts the function of cytotoxic T cells, and leads to decreased protein levels of the oncoproteins E6 and E7 in HPV-transformed cells. Therefore, we investigated the effect of hypoxia on the presentation of HPV16 E6- and E7-derived epitopes in cervical cancer cells and its effect on epitope-specific T cell cytotoxicity. Hypoxia induced downregulation of E7 protein levels in all analyzed cell lines, as assessed by Western blotting. However, contrary to previous reports, no perturbation of antigen processing and presentation machinery (APM) components and HLA-A2 surface expression upon hypoxia treatment was detected by mass spectrometry and flow cytometry, respectively. Cytotoxicity assays performed in hypoxic conditions showed differential effects on the specific killing of HPV16-positive cervical cancer cells by epitope-specific CD8+ T cell lines in a donor- and peptide-specific manner. Effects of hypoxia on the expression of PD-L1 were ruled out by flow cytometry analysis. Altogether, our results under hypoxia show a decreased expression of E6 and E7, but an intact APM, and epitope- and donor-dependent effects on T cell cytotoxicity towards HPV16-positive target cells. This suggests that successful immunotherapies can be developed for hypoxic HPV-induced cervical cancer, with careful choice of target epitopes, and ideally in combination with hypoxia-alleviating measures.

Case Report: Anti-neural cell adhesion molecule 1 antibody-positive encephalitis presenting with schizophrenia-like symptoms and an ovarian teratoma

Autoimmune encephalitis (AE) has been linked to various autoantibodies, with anti-neural cell adhesion molecule 1 (NCAM1) antibodies recently identified in patients with schizophrenia. Their pathogenic potential has been demonstrated in passive transfer experiments in mice. We report the first case of AE associated with anti-NCAM1 antibodies in a 15-year-old female who presented with acute-onset psychiatric symptoms, including delusions, hallucinations, and catalepsy, along with fever and impaired consciousness. Cerebrospinal fluid analysis showed a high IgG index, and electroencephalography revealed generalized slow-wave activity. However, brain magnetic resonance imaging was unremarkable. A pelvic tumor was identified, and adnexectomy confirmed a right mature cystic teratoma. Given the clinical presentation, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was initially suspected, and the patient was treated with intravenous methylprednisolone and intravenous immunoglobulin, resulting in significant improvement. Despite a subsequent relapse of hallucinations, additional immunotherapy led to complete resolution of symptoms. Notably, anti-NMDAR and other well-known neuronal surface antibodies were negative in both serum and cerebrospinal fluid, whereas anti-NCAM1 antibodies were detected. Immunohistochemical analysis confirmed NCAM1 expression in the excised ovarian tissue, and post-treatment serum tests showed the disappearance of anti-NCAM1 antibodies. The concurrent resolution of clinical symptoms and the disappearance of these antibodies support their pathogenic role. The clinical presentation and paraneoplastic association with teratoma closely resemble anti-NMDAR encephalitis, suggesting that anti-NCAM1 antibodies may define a novel form of AE with psychotic manifestations. Further research is needed to clarify their role in neuroinflammatory disorders.

Comprehensive characterization of tumor microenvironment and m6A RNA methylation regulators and its effects on PD-L1 and immune infiltrates in cervical cancer

Understanding the role of N6-adenosine methylation (m6A) in the tumor microenvironment (TME) is important since it can contribute to tumor development. However, the research investigating the association between m6A and TME and cervical cancer is still in its early stages. The aim of this study was to discover the possible relationship between m6A RNA methylation regulators, TME, PD-L1 expression levels, and immune infiltration in cervical cancer. We gathered RNA-seq transcriptome data and clinical information from cervical cancer patients using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. To begin, researchers assessed the differences in m6A regulatory factor expression levels between cervical cancer and normal tissues. Clustering analysis was adapted to assess PD-L1 expression, immunological score, immune cell infiltration, TME, and probable pathways in cervical cancer samples. The majority of m6A regulators were found to be considerably overexpressed in cervical cancer tissues. Using consensus clustering of 21 m6A regulators, we identified two subtypes (clusters 1/2) of cervical cancer, and we found that WHO stage and grade were associated with the subtypes. PD-L1 expression increased dramatically in cervical cancer tissues and was significantly linked to ALKBH5, FTO, METTL3, RBM15B, YTHDF1, YTHDF3, and ZC3H13 expression levels. Plasma cells and regulatory T cells (Tregs) were considerably elevated in cluster 2. Cluster 1 is involved in numerous signature pathways, including basal transcription factors, cell cycle, RNA degradation, and the spliceosome. The prognostic signature-based riskscore (METTL16, YTHDF1, and ZC3H13) was found to be an independent prognostic indicator of cervical cancer. The tumor immune microenvironment (TIME) was linked to m6A methylation regulators, and changes in their copy number will affect the quantity of tumor-infiltrating immune cells dynamically. Overall, our research discovered a powerful predictive signature based on m6A RNA methylation regulators. This signature correctly predicted the prognosis of cervical cancer patients. The m6A methylation regulator could be a critical mediator of PD-L1 expression and immune cell infiltration, and it could have a significant impact on the TIME of cervical cancer.

Comprehensive analyses identify RIPOR2 as a genomic instability-associated immune prognostic biomarker in cervical cancer

Cervical cancer (CC) is a malignancy that tends to have a poor prognosis when detected at an advanced stage; however, there are few studies on the early detection of CC at the genetic level. The tumor microenvironment (TME) and genomic instability (GI) greatly affect the survival of tumor patients via effects on carcinogenesis, tumor growth, and resistance. It is necessary to identify biomarkers simultaneously correlated with components of the TME and with GI, as these could predict the survival of patients and the efficacy of immunotherapy. In this study, we extracted somatic mutational data and transcriptome information of CC cases from The Cancer Genome Atlas, and the GSE44001 dataset from the Gene Expression Omnibus database was downloaded for external verification. Stromal components differed most between genomic unstable and genomic stable groups. Differentially expressed genes were screened out on the basis of GI and StromalScore, using somatic mutation information and ESTIMATE methods. We obtained the intersection of GI- and StromalScore-related genes and used them to establish a four-gene signature comprising RIPOR2, CCL22, PAMR1, and FBN1 for prognostic prediction. We described immunogenomic characteristics using this risk model, with methods including CIBERSORT, gene set enrichment analysis (GSEA), and single-sample GSEA. We further explored the protective factor RIPOR2, which has a close relationship with ImmuneScore. A series of in vitro experiments, including immunohistochemistry, immunofluorescence, quantitative reverse transcription PCR, transwell assay, CCK8 assay, EdU assay, cell cycle detection, colony formation assay, and Western blotting were performed to validate RIPOR2 as an anti-tumor signature. Combined with integrative bioinformatic analyses, these experiments showed a strong relationship between RIPOR2 with tumor mutation burden, expression of genes related to DNA damage response (especially PARP1), TME-related scores, activation of immune checkpoint activation, and efficacy of immunotherapy. To summarize, RIPOR2 was successfully identified through comprehensive analyses of the TME and GI as a potential biomarker for forecasting the prognosis and immunotherapy response, which could guide clinical strategies for the treatment of CC patients.

A Novel Prognostic Risk Model for Cervical Cancer Based on Immune Checkpoint HLA-G-Driven Differentially Expressed Genes

Human leukocyte antigen G (HLA-G) is a potential checkpoint molecule that plays a key role in cervical carcinogenesis. The purpose of this study was to construct and validate a prognostic risk model to predict the overall survival (OS) of cervical cancer patients, providing a reference for individualized clinical treatment that may lead to better clinical outcomes. HLA-G-driven differentially expressed genes (DEGs) were obtained from two cervical carcinoma cell lines, namely, SiHa and HeLa, with stable overexpression of HLA-G by RNA sequencing (RNA-seq). The biological functions of these HLA-G-driven DEGs were analysed by GO enrichment and KEGG pathway using the “clusterProfiler” package. The protein-protein interactions (PPIs) were assessed using the STRING database. The prognostic relevance of each DEG was evaluated by univariate Cox regression using the TCGA-CESC dataset. After the TCGA-CESC cohort was randomly divided into training set and testing set, and a prognostic risk model was constructed by LASSO and stepwise multivariate Cox regression analysis in training set and validated in testing set or in different types of cervical cancer set. The predictive ability of the prognostic risk model or nomogram was evaluated by a series of bioinformatics methods. A total of 1108 candidate HLA-G-driven DEGs, including 391 upregulated and 717 downregulated genes, were obtained and were enriched mostly in the ErbB pathway, steroid biosynthesis, and MAPK pathway. Then, an HLA-G-driven DEG signature consisting of the eight most important prognostic genes CD46, LGALS9, PGM1, SPRY4, CACNB3, PLIN2, MSMO1, and DAGLB was identified as a key predictor of cervical cancer. Multivariate Cox regression analysis showed that this signature is an independent risk factor for the overall survival of CESC patients. Kaplan-Meier survival analysis showed that the 5-year overall survival rate is 23.0% and 84.6% for the high-risk and low-risk patients, respectively (P<0.001). The receiver operating characteristic (ROC) curve of this prognostic model with an area under the curve (AUC) was 0.896 for 5 years, which was better than that of other clinical traits. This prognostic risk model was also successfully validated in different subtypes of cervical cancer, including the keratinizing squamous cell carcinoma, non-keratinizing squamous cell carcinoma, squamous cell neoplasms, non-squamous cell neoplasms set. Single-sample gene set enrichment (ssGSEA) algorithm and Tumor Immune Dysfunction and Exclusion (TIDE) analysis confirmed that this signature influence tumour microenvironment and immune checkpoint blockade. A nomogram that integrated risk score, age, clinical stage, histological grade, and pathological type was then built to predict the overall survival of CESC patients and evaluated by calibration curves, AUC, concordance index (C-index) and decision curve analysis (DCA). To summarize, we developed and validated a novel prognostic risk model for cervical cancer based on HLA-G-driven DEGs, and the prognostic signature showed great ability in predicting the overall survival of patients with cervical cancer.

Infiltration Patterns of Cervical Epithelial Microenvironment Cells During Carcinogenesis

BackgroundLocal cellular microenvironment plays a crucial role in the HPV-induced cervical malignant transformation. Characterization of the dynamic infiltration changes of microenvironment cells during cervical carcinogenesis would contribute to a better understanding of involved mechanisms.MethodsThree public gene expression datasets of cervical squamous epithelium samples were collected and combined. We applied seven up-to-date computational methods for infiltrating estimation and compared their results (CD4+ and CD8+ T cells) to the known fraction. After benchmarking the applied methods, the cell filtration patterns were determined and clustered through fuzzy c-means algorithm.ResultsMost methods displayed better performance in predicting the abundance of CD4+ T cell than that of CD8+ T cell. The infiltration patterns of 33 microenvironment cell types (including 31 immune cells and 2 non-immune cells) were determined, and five immune cell clusters with distinct features were then derived. Meanwhile, opposite changes in abundance were observed between the activated and resting state of some immune cells from the progression perspective.ConclusionsBased on characteristics and evaluation performance of different methods, as well as previous findings, for the first time we provide a comprehensive overview of the infiltration patterns of microenvironment cells throughout cervical cancer progression.

Dissecting the Single-Cell Transcriptome Network of Immune Environment Underlying Cervical Premalignant Lesion, Cervical Cancer and Metastatic Lymph Nodes

Cervical cancer (CC) is one of the most common malignancy in women worldwide. It is characterized by a natural continuous phenomenon, that is, it is in the initial stage of HPV infection, progresses to intraepithelial neoplasia, and then develops into invasion and metastasis. Determining the complexity of tumor microenvironment (TME) can deepen our understanding of lesion progression and provide novel therapeutic strategies for CC. We performed the single-cell RNA sequencing on the normal cervix, intraepithelial neoplasia, primary tumor and metastatic lymph node tissues to describe the composition, lineage, and functional status of immune cells and mesenchymal cells at different stages of CC progression. A total of 59913 single cells were obtained and divided into 9 cellular clusters, including immune cells (T/NK cells, macrophages, B cells, plasma cells, mast cells and neutrophils) and mesenchymal cells (endothelial cells, smooth muscle cells and fibroblasts). Our results showed that there were distinct cell subpopulations in different stages of CC. High-stage intraepithelial neoplasia (HSIL) tissue exhibited a low, recently activated TME, and it was characterized by high infiltration of tissue-resident CD8 T cell, effector NK cells, Treg, DC1, pDC, and M1-like macrophages. Tumor tissue displayed high enrichment of exhausted CD8 T cells, resident NK cells and M2-like macrophages, suggesting immunosuppressive TME. Metastatic lymph node consisted of naive T cell, central memory T cell, circling NK cells, cytotoxic CD8+ T cells and effector memory CD8 T cells, suggesting an early activated phase of immune response. This study is the first to delineate the transcriptome profile of immune cells during CC progression using single-cell RNA sequencing. Our results indicated that HSIL exhibited a low, recently activated TME, tumor displayed immunosuppressive statue, and metastatic lymph node showed early activated phase of immune response. Our study enhanced the understanding of dynamic change of TME during CC progression and has implications for the development of novel treatments to inhibit the initiation and progression of CC.

Use of Single Cell Transcriptomic Techniques to Study the Role of High-Risk Human Papillomavirus Infection in Cervical Cancer

High-risk human papillomavirus (hrHPV) infection has been associated with a higher probability of progression to cervical cancer. However, several extensive studies have reported that the presence of hrHPV can lead to a better prognosis, but the mechanism of how this occurs is unclear. In this study, microbiological analysis was used to identify HPV infection as a factor for the prognosis of patients with cervical squamous cell carcinoma (CSCC). Comparing the interactions of HPV+ and HPV- malignant cells with immune cells as well as the trajectory of malignant cells either with or without HPV, we found that most of the HPV+ cells are well differentiated while HPV- cells appear to be hypo-fractionated. Using transcriptomic and immunostaining data, we validated a set of unfavourable molecules in the HPV- CSCC cells, including KRT16, ITGB1, CXCR1, VEGFA, CRCT1 and TNFRSF10B/DR5. This study provides a basis for the development of a rational post-operative follow-up programme and the development of an appropriate treatment plan for patients with cervical cancer.

The role of tumor-associated macrophages in HPV induced cervical cancer

Human papillomavirus (HPV), a double-stranded DNA virus linked to various malignancies, poses a significant global public health challenge. In cervical cancer, persistent infection with high-risk HPV genotypes, particularly HPV-16 and HPV-18, initiates immune evasion mechanisms within the tumor microenvironment. The polarization of tumor-associated macrophages (TAMs) from M1 to M2 phenotypes promotes cervical carcinogenesis, metastasis, and therapeutic resistance via establishing an immunosuppressive microenvironment. This review provides a comprehensive overview of HPV-induced immune evasion pathways, including MHC downregulation, T-cell impairment, regulatory T cell induction, and cGAS-STING pathway inhibition. Furthermore, describe the pivotal role of TAMs in cervical cancer progression, focusing on their phenotypic plasticity, pro-tumoral functions, and potential as therapeutic targets. By elucidating these cellular and molecular dynamics, this review aims to support advanced research. Targeting TAM polarization through immunotherapies and nanomedicine-based strategies represents a promising strategy for enhancing patient outcomes.

Predicting immunotherapy efficacy in endometrial cancer: focus on the tumor microenvironment

Immunotherapy represents a groundbreaking therapeutic approach, based on the immune system’s intrinsic capacity to interfere with tumor progression, that opens the horizons in the treatment of endometrial cancer. However, the clinical efficacy of immunotherapy is hampered by the development of resistance in patients. The resistance to immunotherapy is multifactorial mechanism, encompassed genetic and epigenetic alterations in tumor cells modulating immune checkpoint molecules, resulted in escaping immune surveillance. The tumor microenvironment can orchestrate an immunosuppressive milieu, attenuating the immune response and facilitating tumor progression. To overcome immunotherapeutic resistance in endometrial cancer we must bring to light the mechanisms of intricate interplay between neoplastic cells, the host immune system, and the tumor microenvironment. The identification of predictive biomarkers for immunotherapeutic response and the innovative agents capable of reversing resistance pathways must be developed. Our review summarizes accumulated data on the role of cells of the tumor microenvironment and their regulatory molecules in the mechanisms underlying therapeutic effects of immune checkpoint inhibitors, including resistance to therapy. Major question we raise here – which group of patients is the most favorable to achieve durable immunotherapy response in endometrial cancer?

m6A Regulator-Mediated Tumour Infiltration and Methylation Modification in Cervical Cancer Microenvironment

BackgroundN6-methyladenosine (m6A) is the most abundant internal mRNA modification in eukaryotic cells. There is accumulating evidence that m6A methylation can play a significant role in the early diagnosis and treatment of cancers. However, the mechanism underlying the involvement of m6A in cervical cancer remains unclear.MethodsHere, we examined the m6A modification patterns of immune cells in the tumour microenvironments (TMEs) of 306 patients with cervical cancer from The Cancer Genome Atlas dataset and analysed the relations between them according to 32 m6A regulators. Immune infiltration in the TME of cervical cancer was analysed using the CIBERSORT algorithm and single-sample gene set enrichment analysis. The m6Ascore was structured though principal component analysis.ResultsTwo different m6A modification patterns were detected in 306 patients with cervical cancer, designated as m6Acluster A and B. The immune cell infiltration characteristics and biological behaviour differed between the two patterns, with m6Acluster A showing a higher level of immune infiltration. The samples were also divided into two genomic subtypes according to 114 m6A regulatory genes shown to be closely correlated with prognosis on univariate Cox regression analysis. Survival analysis showed that gene cluster B was related to better survival than gene cluster A. Most of the m6A regulators showed higher expression in gene cluster B than in gene cluster A. Single-sample gene set enrichment analysis indicated a higher level of immune cell infiltration in gene cluster A. The m6Ascore signature was examined to determine the m6A modification patterns in cervical cancer. Patients with a high m6Ascore showed better survival, while the low m6Ascore group had a higher mutation frequency and better response to treatment.ConclusionsThis study showed that m6A modification patterns play important roles in cervical cancer. Analysis of m6A modification patterns will yield an improved understanding of the TME in cervical cancer, and facilitate the development of better immunotherapy strategies.

Adverse drug reaction assessment of pembrolizumab in cervical cancer treatment: a real-world pharmacovigilance study using the FAERS database

ObjectiveAdvanced cervical cancer remains associated with high mortality rates. While pembrolizumab has improved clinical outcomes in cervical cancer, the therapeutic efficacy in advanced stages is often compromised by immune-related adverse events (irAEs). This study aimed to systematically analyze pembrolizumab-associated adverse events (AEs) in cervical cancer using the FDA Adverse Event Reporting System (FAERS) database, providing new insights for optimizing clinical practice.MethodsAE reports related to pembrolizumab in cervical cancer were extracted from the FAERS database (Q1 2016 to Q4 2024). Disproportionality analyses were performed using multiple algorithms, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). AEs were classified by system organ class (SOC) and preferred term (PT) based on the Medical Dictionary for Regulatory Activities (MedDRA), then ranked by frequency and signal strength.ResultsA total of 646 pembrolizumab-related AE reports in cervical cancer were identified. Age distribution peaked at 45–65 years cohort (32.75%), followed by 18–44 years (12.85%), 66–75 years (11.76%), and >75 years (4.64%). Among 270 AE reports with documented onset timelines, events predominantly occurred 3–6 months after pembrolizumab initiation (n=114, 41.36%). Clinical outcomes were categorized as other (52.80%), hospitalization (27.00%), death (10.25%), unknown (6.06%), life-threatening (2.77%), and disability (1.12%). Predominant AEs involved hematologic, endocrine, dermatologic, neurologic, gastrointestinal, urinary, and reproductive systems.ConclusionThis real-world pharmacovigilance study systematically characterizes pembrolizumab-associated AEs in cervical cancer, identifying high-signal events such as hematologic disorders, endocrine dysfunction, and dermatologic toxicities. These findings provide critical evidence for risk stratification and safety monitoring in clinical practice, emphasizing the need for organ-specific vigilance during the 3–6 months treatment window.

IL 15 enhances preclinical efficacy of anti-core 1 O-glycans monoclonal antibody NEO-201 against human endometrial and ovarian cancer

Background Resistance of gynecological cancers to immunotherapy is due to their ability to impair the cytotoxic activity of immune cells. One strategy to overcome this resistance is the combination of different types of immunotherapies with different mechanisms of action and different targets. The disruption of O-glycosylation pathway in ovarian and endometrial cancer is associated with cancer growth, metastasis, and poor prognosis. Methods In this study we treated in vitro endometrial and ovarian human cancer cell lines with the combination of the monoclonal antibody (mAb) NEO-201 and IL-15 to overcome the resistance of gynecological cancers to immunotherapy. The combination was also used in vivo to treat mice bearing human ovarian cancer. NEO-201 is a humanized IgG1 mAb that binds to core 1 and/or extended core 1 O-glycans expressed by human cancer cells (including different ovarian cancer subtypes), as well as non-cancerous CD15 + granulocytes and immunosuppressive cells. NEO-201 can mediate the killing of its target cells through different mechanisms of action, including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). One strategy to enhance ADCC mediated by mAbs is to boost natural killer (NK) cells with IL-15. A previous study showed that IL-15 superagonist complex (N-803) enhanced ADCC activity mediated by NEO-201 in vitro against several human carcinoma cells, by modulating NK cells activation and cytotoxicity. Results In this study we demonstrated that IL-15 enhanced ADCC mediated by NEO-201 in vitro against human endometrial and ovarian cancer cell lines expressing NEO-201 target antigen, and that the combination of IL-15 and NEO-201, using purified human NK cells as effectors, had a modest effect in prolonging the survival of mice bearing human ovarian cancer, compared to IL-15 or NEO-201 alone. Conclusions The ability of IL-15 to enhance NEO-201 efficacy, with NK cells as effectors, supports the hypothesis of combining NEO-201 and IL-15 with NK cell therapy (i.e. IL-15-secreting CAR-NK cells with a longer IL-15 in vivo half-life and stronger NK activity) for the treatment of gynecological cancers expressing O-glycans recognized by NEO-201.

Neoadjuvant chemotherapy-induced immune remodeling in ovarian cancer: implications for TIL dynamics and combination immunotherapy

Ovarian cancer (OC), particularly high-grade serous ovarian cancer (HGSOC), is among the most lethal gynecologic malignancies, with its therapeutic challenges primarily stemming from a distinctly immunosuppressive tumor immune microenvironment (TIME). Neoadjuvant chemotherapy (NACT) has emerged as a crucial treatment strategy for advanced ovarian cancer; nevertheless, its impact on the tumor microenvironment—especially on tumor-infiltrating lymphocytes (TILs)—is not yet fully understood. As central mediators of antitumor immune responses, the density, composition, and dynamic changes of TILs are strongly associated with chemotherapy response and patient prognosis. Notably, spatial omics studies further revealed that, after NACT, a subset of CD8+ T cells can be confined within “myelonets” microdomains organized by myeloid cells, where interactions such as NECTIN2–TIGIT impose spatial restriction and induce functional exhaustion of T cells, thereby compromising their effective tumor killing. This review aims to systematically summarize the baseline characteristics and heterogeneity of lymphoid- and myeloid-derived TILs in ovarian cancer, elucidate the mechanisms underlying immune remodeling induced by NACT and their complex relationships with clinical outcomes, and further discuss combination therapeutic strategies and biomarker development based on dynamic TIL changes to enhance the clinical application of precision immunotherapy.

Decoding inflammatory regulation in ovarian cancer at single-cell resolution

Ovarian cancer(OC) poses a significant clinical challenge due to its frequent peritoneal dissemination and development of chemotherapy resistance, contributing to poor patient outcomes. Chronic inflammation is a pivotal driver of disease initiation and progression. While traditional population-level studies fail to capture cellular heterogeneity, recent advances in single-cell technologies including scRNA-seq, spatial transcriptomics, and multi-omics, have enabled high-resolution analysis of inflammatory regulation within the ovarian cancer microenvironment(OCME). This review synthesizes how single-cell approaches have elucidated inflammation-driven remodeling of OCME components, immune cell signaling pathways, and dynamic inflammatory-immune interactions. Focusing on the “dual microenvironments” of ovarian cancer, we discuss mechanisms of immune suppression, stromal reprogramming, and therapy resistance, along with current progress and challenges in translating these insights into precise diagnostic, targeted therapeutic, and immunotherapeutic strategies.

CAR-NK cell for gynecological cancers: immune microenvironment remodeling and immunotherapeutic strategies

Gynecological malignancies, including ovarian, cervical, and endometrial cancers, represent a substantial global health burden, contributing significantly to morbidity and mortality among women. Despite advancements in therapeutic strategies, outcomes for many patients remain suboptimal due to challenges such as late-stage detection and resistance to standard treatments. The advent of chimeric antigen receptor (CAR)-engineered natural killer (NK) cells has introduced a cutting-edge immunotherapy option. This review provides an in-depth exploration of the development of CAR-NK cells, emphasizing their sources, design methodologies, and applications in managing gynecological cancers. It also examines current obstacles and outlines innovative strategies to improve the effectiveness and safety of CAR-NK cell-based therapies. Furthermore, we discuss prospective advancements, highlighting the importance of ongoing research and technological innovation to unlock the full potential of CAR-NK cells in the fight against gynecological cancers.

Natural killer cell exhaustion in ovarian cancer: from molecular suppression to therapeutic revival

Ovarian cancer remains one of the most lethal gynecologic malignancies, largely due to its late-stage diagnosis and the establishment of an immunosuppressive tumor microenvironment (TME). Natural killer (NK) cells, key effectors of innate immunity, exhibit impaired cytotoxicity within this hostile niche. The dysfunction arises from multiple mechanisms, including suppression by immunosuppressive cytokines (TGF-β, MUC16), shedding of activating ligands (MICA/B, B7-H6, CD155), overexpression of inhibitory immune checkpoints (PD-1, TIGIT), and metabolic reprogramming shaped by glucose and lipid competition. Recent advances in NK cell–based immunotherapies—such as cytokine modulation, adoptive NK transfer, and checkpoint blockade—have demonstrated potential to reverse NK exhaustion and enhance antitumor efficacy. In this review, we systematically dissect the molecular and cellular pathways underlying NK cell suppression in ovarian cancer and evaluate emerging strategies to reinvigorate NK-mediated immunosurveillance.

The prognostic significance of primary tumor laterality in malignant ovarian teratomas: a 10-year experience at a single institution

Background Approximately 95% of ovarian teratomas are classified as benign, with only about 5% being malignant. Nevertheless, no research has previously explored the connection between primary tumor laterality and prognostic outcomes among malignant ovarian teratoma (MOT) patients. Our aim was to investigate the association of primary tumor laterality with prognosis in MOT. Methods This retrospective study enrolled patients with MOT from The Affiliated Hospital of Qingdao University from January 2012 to December 2021. The primary outcome was progression-free survival (PFS) and overall survival (OS). The prognostic difference between left-sided, right-sided and bilateral groups was investigated using Kaplan-Meier analyses and Cox proportional hazards regression analyses. Results A total of 51 eligible patients with MOT were included with a median age of 52 years. Among the patients with MOT, the multivariate Cox regression analyses showed that right-sided (hazard ratio [HR]=0.01; 95% confidence interval [CI]=0.00-0.04; P = 0.01) MOT was associated with better PFS, compared with left-sided MOT (HR = 1.00). Kaplan-Meier analyses also showed that the primary tumor laterality had a significant prognostic effect in MOT. Conclusion Among patients with MOT, those with unilateral tumors, particularly right-sided ones, had a significantly better prognosis than those with bilateral tumors. Gynecologic oncologists might account for the prognostic impact of primary tumor laterality in MOT and tailor treatment and surveillance accordingly.

Chronic stress drives ovarian cancer progression via myeloid-derived suppressor cells infiltration and Notch signaling pathway activation

Background Ovarian cancer (OC) is a leading cause of cancer-related death among women, with elevated levels of stress hormones linked to OC progression and immune evasion in the tumor microenvironment (TME). Chronic psychosocial stress has been associated with the expansion of immunosuppressive myeloid-derived suppressor cells (MDSCs), which promote tumor growth and negatively impact patient outcomes. This study tested how chronic daily restraint stress affected ovarian cancer progression, Notch signaling, and MDSCs in the OC TME. We hypothesized that chronic stress increases MDSCs infiltration in the TME, enhances Notch signaling in OC cells, and promotes cancer progression. Methods Female C57BL/6 mice were injected with ID8 Luc or IG10 Luc OC cells and subjected to daily restraint stress. We also isolated bone marrow from naïve C57BL/6 mice to differentiate myeloid cell precursors into MDSCs. These cells were then exposed to norepinephrine (NE), epinephrine (EPI), or corticosterone (CC). To further evaluate the effects of stress hormones on the dysregulation of the Notch signaling pathway, we treated OC cells with NE, EPI, or CC. Results Chronic daily restraint stress increased MDSCs infiltration and enriched polymorphonuclear (PMN)-MDSCs in the TME and bone marrow in both models. Ex vivo studies demonstrated an increased enrichment of PMN-MDSCs along with a reduction of mononuclear (M)-MDSCs in the groups treated with stress hormones, particularly CC. Our results showed that stress hormones significantly increased the expression of notch intracellular domain (NICD) in OC cells. Additionally, we observed increased mRNA levels of Notch1, Jagged2, and Hes1, along with elevated NICD and HES1 protein levels, mediated by CC-induced GSK3β phosphorylation. Pharmacological inhibition of NICD and g Luc ocorticoid receptors blocked the CC-induced Notch pathway activation via GSK3β phosphorylation. Moreover, tumors from mice subjected to restraint stress had elevated expression of Notch1 , Jagged 2 , NICD, HES1 , GR, ADRB2, and pS9-GSK3β. Conclusion These data indicate that chronic stress leads to MDSCs infiltration and suppressive activity, which contributes to an immunosuppressive TME and OC progression.

A multidimensional data-driven approach to surgical plan optimization and postoperative residual tumor prediction in ovarian cancer

Backgrounds Ovarian cancer represents a deadly gynecological malignancy, with surgical treatment being a key component of its management. We sought to integrate clinical characteristics and ascites immune microenvironment features into a deep learning model to predict postoperative residual tumor status and assist in surgical decision-making. Methods 118 FIGO III/IV high-grade serous ovarian cancer (HGSOC) patients treated at Peking University Third Hospital (2019-2024) were enrolled. Clinical characteristics, surgical methods, and postoperative residual tumor status were collected. Ascites samples were processed via density gradient centrifugation and flow cytometry. Deep learning model was built by fusing clinical and immune data, and its performance was validated under a gradient of feature quantities (5–45 features) to optimize feature selection. Model performance was comprehensively evaluated on a test set (20% of the dataset) using metrics including accuracy, precision, recall, and F1 score, and compared with traditional machine learning models (random forest, XGBoost, et al). Confusion matrices and probability heatmaps were used for visual analysis. For model interpretability, we presented feature importance and results from SHAP analysis. Results Our model achieved 70.83% accuracy, 71.21% precision, 70.83% recall, and 70.89% F1 score on the test set, outperforming traditional machine learning models: random forest (accuracy: 64.6%, precision: 65.1%, recall: 64.6%, F1 score: 66.4%), XGBoost (accuracy: 66.7%, precision: 67.0%, recall: 66.7%, F1 score: 66.6%), and logistic regression (accuracy: 58.3%, precision: 59.0%, recall: 58.4%, F1 score: 58.2%). It demonstrated strong performance in identifying high-risk R2 cases but showed limitations in differentiating between R0 and R1 statuses. Probability heatmaps visualized the distribution of R0, R1, and R2 probabilities under different surgical methods, facilitating intuitive clinical reference. Interpretability analysis via permutation feature importance and SHAP highlighted the critical role of surgical methods and specific immune microenvironment features in predictive outcomes. Conclusion This study developed a novel deep learning-based model to predict postoperative residual tumor probability, integrating clinical and immune microenvironment data. While the model excelled in identifying high-risk cases (e.g., R2), further optimization is needed to improve R0 and R1 differentiation. Future research should expand datasets and integrate multi-omics data to enhance predictive accuracy and clinical applicability.

Immunological mechanisms and antibody-drug conjugates targeting B7-H3 and B7-H4 in ovarian cancer

Ovarian cancer remains the most lethal gynecologic malignancy, with immune evasion a major driver of therapeutic resistance and disease progression. Among novel targets, the immune checkpoint molecules B7-H3 and B7-H4 have been recognized for their potent immunosuppressive roles and selective overexpression in ovarian tumors. This review examines the immunological mechanisms shaping B7-H3 and B7-H4 activity within the ovarian tumor microenvironment, their role in facilitating immune escape, and their association with poor clinical outcomes. The development of antibody–drug conjugates targeting B7-H3 and B7-H4 offers a novel approach to deliver potent cytotoxic therapy with tumor specificity. Preclinical models and early-phase clinical studies demonstrate encouraging antitumor activity, including in treatment-resistant disease. By integrating advances in tumor immunobiology and ADC technology, this review explores how targeting B7-H3 and B7-H4 could reshape therapeutic strategies in ovarian cancer.

The immunotherapy era in ovarian clear cell carcinoma: current evidence and future perspective

Ovarian clear cell carcinoma (OCCC) is a rare, aggressive epithelial ovarian cancer subtype, accounting for approximately 10% of cases and associated with a poor prognosis due to chemoresistance and unique tumor biology. OCCC is frequently linked to endometriosis and characterized by mutations in ARID1A and PIK3CA , hyperactivation of the PI3K/Akt/mTOR pathway, and overexpression of VEGF, HIF-1α, and IL-6. These features drive tumor proliferation, angiogenesis, immune evasion, and resistance to platinum-based chemotherapy. The tumor microenvironment of OCCC is highly immunosuppressive, with infiltration of regulatory T cells, tumor-associated macrophages, and upregulation of immune checkpoint molecules, such as PD-1, PD-L1, and LAG-3. These characteristics suggest that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and could be an attractive target for therapeutic intervention. Despite the typical composition of the immunosuppressive tumor microenvironment in ovarian cancer, until now overall the results of trials testing immune checkpoint inhibitors so far have been disappointing. It is interesting to note instead that several subgroup analyses reported exceptional OCCC sensitivity to ICIs. Indeed, current and preliminary trials exploring ICIs, anti-angiogenic agents, and combinatorial therapies in OCCC show promising outcomes. Strategies targeting multiple pathways, including VEGF, IL-6, HIF-1α, and HDAC6, alongside ICIs, are under investigation to overcome resistance mechanisms. Additionally, IL-10 inhibition or ferroptosis pathway activation offers novel therapeutic potential. Personalized, biomarker-driven approaches, targeting ARID1A and PIK3CA mutations or combining immune and anti-angiogenic agents, are gaining traction in OCCC management. This review highlights OCCC molecular underpinnings and therapeutic challenges, emphasizing the need for innovative, multi-targeted strategies. Advances in understanding genetic-immunological interplay in OCCC may enable more effective and durable treatments and improved patient outcomes.

VISTA+ follicular regulatory T cells modulate the function of effector immune cells: implications for ovarian cancer immune escape

Background As key regulatory cells, the impact of follicular regulatory T (Tfr) cells, whose function is regulated by V-domain Ig suppressor of T cell activation (VISTA), on downstream immune cells remains unclear. These cellular-level regulatory mechanisms are closely associated with the development of immune escape in ovarian cancer, a disease characterized by severe effector immune cell dysfunction in the tumor microenvironment. This study aims to elucidate the regulatory effects of VISTA + Tfr cells on the functions of CD8 + T cells, CD4 + CD25 − T cells, and B cells, and to reveal their significance in the immune escape of ovarian cancer. Methods VISTA-overexpressing and silenced Tfr cell models were constructed in vitro . Through co-culture experiments, CFSE proliferation assays, ELISA, and flow cytometry were employed to investigate the effects of VISTA + Tfr cells on CD8 + T cell proliferation, effector cytokine secretion, and activation status; their regulation of CD4 + CD25 − T cell proliferation, cytokine secretion, and Th cell differentiation; and their impact on B cell proliferation and antibody secretion. Results VISTA + Tfr cells significantly inhibited CD8 + T cell proliferation, secretion of effector cytokines (IL-2, IFN-γ), and expression of the activation marker CD69, while upregulating their exhaustion molecules (PD-1, CTLA-4). They skewed the differentiation of CD4 + CD25 − T cells toward a Th2 phenotype and suppressed Th1 and Th17 cell differentiation. Furthermore, they specifically inhibited IgE secretion by B cells, with no significant effect on other antibodies. Conclusion VISTA + Tfr cells multi-dimensionally suppress the function of effector immune cells, providing experimental evidence for the potential role of VISTA-targeted strategies in improving anti-tumor immune responses in ovarian cancer.

Macrophages and neutrophils in ovarian cancer microenvironment

Ovarian cancer (OC) remains one of the most aggressive gynecological malignancies, with a five-year survival rate below 45% despite the recent advances in the introduction of targeted therapy. Moreover, immunotherapy, such as immune checkpoint inhibitors, does not improve the survival of OC patients. Lack of sufficient knowledge in understanding the complexity of the tumor microenvironment likely confers the treatment ineffectiveness. Recently, tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) have garnered research attention as they shape the tumor immune microenvironment, which plays a crucial role in disease progression and treatment response. This article reviews the complex roles of these innate immune cells in OC progression. TAMs represent a significant component of the immune infiltrate in OC, exhibiting considerable functional plasticity and can shift between anti-tumoral (M1) and pro-tumoral (M2) phenotypes. M2-like TAMs typically predominate in the tumor microenvironment, which aids in the development of immune suppression and disease progression. They also contribute to chemoresistance and metastasis; hence, their presence in tumors is associated with a worse prognosis. TANs, like TAMs, exhibit N1/N2 polarization and influence tumor progression through the formation of neutrophil extracellular traps. Understanding the biological interactions between various immune cells and cancer cells may offer new therapeutic opportunities. This review sheds light on the dynamic ecological transformation of the OC tumor microenvironment and highlights the potential of targeting TAM/TAN-mediated processes to improve OC treatment outcomes.

Advances in PD-1 and CTLA-4 dual-target immunotherapy for ovarian cancer

Ovarian cancer(OC) remains a major threat to women’s health, ranking among the top gynecologic malignancies in both incidence and mortality. Current clinical management continues to center on cytoreductive surgery combined with a multidisciplinary approach incorporating chemotherapy, targeted therapy, and immunotherapy. Notably, while single-agent immunotherapy has demonstrated limited efficacy in recurrent OC, recent breakthrough advances in dual-target immunotherapy have brought new hope for advanced-stage and recurrent patients. Clinical evidence indicates that programmed death-1/cytotoxic T-lymphocyte-associated protein 4 (PD-1/CTLA-4) dual immune checkpoint blockade strategies (e.g., durvalumab plus tremelimumab, nivolumab plus ipilimumab) exhibit differential therapeutic effects: durable treatment responses have been observed in recurrent/platinum-resistant advanced OC, while neoadjuvant applications have significantly improved complete resection rates. However, these therapeutic benefits demonstrate marked heterogeneity across different histological subtypes. The review of current research reveals several critical issues: first, the safety profile of dual immunotherapy requires further characterization; second, data on first-line treatment for advanced OC remain scarce; and third, optimal treatment strategies have yet to be established. Nevertheless, multiple ongoing clinical trials are paving the way for future research directions, including optimization of combination regimens and exploration of predictive biomarkers. In conclusion, despite existing challenges, dual-target immunotherapy has demonstrated clinically meaningful benefits, offering new therapeutic options for advanced and recurrent OC patients and heralding a new era of combination immunotherapy in OC treatment. Future large-scale clinical studies are warranted to further validate efficacy and establish individualized precision treatment strategies.

Engineered NK92 cell-derived exosomes inhibit ovarian cancer progression by degrading GPRC5A

Background Natural killer (NK) 92 (NK92) cells are critical immune-effectors with established roles in treating metastatic and hematological malignancies. Owing to the substantial adverse effects, including cytokine release syndrome, associated with NK92 cell therapy, research interest has pivoted toward the safer and potentially more efficient exosome-based approaches. However, the composition, properties, and functions of NK92 cell-derived exosomes remain largely unknown. Methods In this study, NK92 cell-derived exosomes were isolated via ultracentrifugation. Small RNA sequencing and proteomic sequencing were performed on both the cells and their exosomes. To enhance exosome targeting to tumor cells, the tLyP-1 targeting peptide was displayed on NK92 cell surfaces through genetic engineering. The mechanism underlying tumor therapy mediated by NK92 cell-derived exosomes was investigated through in vitro and in vivo experiments. Additionally, we designed a cholesterol-modified ABCB1 siRNA that adsorbs onto exosome surfaces and enters recipient cells to silence target genes. Results First, small RNA sequencing and proteomic analysis of NK92 cells and NK92 cell-derived exosomes revealed that the exosomes retained the anti-tumor activity of parental NK cells, inhibiting tumor progression by modulating apoptosis, proliferation, and metastasis. Second, tLyP-1-modified exosomes exhibited enhanced tumor-targeting specificity and exerted anti-tumor effects via the miR-31-5p- GPRC5A axis. Furthermore, NK92 cell-derived exosomes effectively delivered ABCB1 siRNA into recipient cells, mediating efficient gene silencing to sensitize chemoresistant ovarian cancer cells to therapeutic agents. Conclusion Overall, this study provides a novel strategy to treat ovarian cancer through the preparation of genetically modified NK92 cell-derived exosomes loaded with RNA interference.

Knockdown of TOP2A reverses cisplatin resistance in ovarian cancer by inhibiting EMT via ferroptosis mediated by the TP53/GPX4/SLC7A11 axis

Introduction Cisplatin resistance is a major challenge in ovarian cancer therapy, particularly for high-grade serous ovarian cancer (HGSOC). DNA topoisomerase IIα (TOP2A) relates to cancer drug resistance, yet its role and molecular mechanisms in ovarian cancer cisplatin resistance remain unclear. Methods TOP2A expression was detected in HGSOC tissues and cisplatin-resistant cells (SKOV3-DDP, OVCAR3-DDP). Functional assays combined with TOP2A knockdown evaluated cisplatin sensitivity and malignant phenotypes (proliferation, invasion, migration) in resistant cells. RNA-seq and GEO cisplatin resistance dataset (GSE214302) validated TOP2A’s role in cisplatin resistance, prognostic value, and associations with TP53, GPX4, SLC7A11. Molecular docking/Co-IP confirmed TOP2A-TP53 interaction. Fer-1 and TP53 knockdown clarified TP53/GPX4/SLC7A11 axis regulation of ferroptosis and EMT, and an in vivo xenograft tumor model validated these findings. Results TOP2A is highly expressed in HGSOC tissues and cisplatin-resistant cells, with high levels strongly associated with tumor progression (advanced stage, high grade, lymph node metastasis) and poor prognosis. RNA-seq shows TOP2A correlates with TP53, GPX4, SLC7A11.GEO dataset analysis confirms all four associate with cisplatin resistance. SLC7A11 and TOP2A are effective resistance biomarkers, and high TOP2A predicts shorter progression-free survival. Molecular assays verify direct TOP2A-TP53 interaction. Functional experiments reveal TOP2A knockdown enhances cisplatin sensitivity, inhibits malignancy, activates ferroptosis, and suppresses EMT via the TP53/GPX4/SLC7A11 axis. This effect is reversed by Fer-1 or TP53 knockdown, with mechanisms validated in vivo . Conclusion TOP2A represents a potential prognostic biomarker and therapeutic target for cisplatin resistance in ovarian cancer (OC), as it regulates ferroptosis and EMT via the TP53/GPX4/SLC7A11 axis, which is mediated by its direct interaction with TP53. This thus provides a novel direction for treating cisplatin-resistant OC.

Enhanced anti-tumor efficacy of tumor-infiltrating lymphocytes by GITR agonist in ovarian cancer

Background Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TILs) is a personalized immunotherapy that has shown promising clinical results in various tumor types. Although TILs are associated with improved survival in patients with ovarian cancer (OC), their therapeutic efficacy remains limited. Therefore, novel strategies to enhance the anti-tumor activity of TILs are needed to improve outcomes in OC treatment. Methods Single cells were isolated from tumor tissues of patients with high-grade serous carcinoma (HGSC) and expanded for 14 days in the presence of IL-2 under four different conditions: (1) control (W), (2) PD-1 antagonist (WI), (3) PD-1 antagonist + IL-15 + IL-21 (WIO), and (4) PD-1 antagonist + IL-15 + IL-21 + GITR-agonist (WIOG). Following validation of TIL purity and activation phenotypes by flow cytometry, RNA sequencing was performed to elucidate the underlying mechanisms. In vitro efficacy was assessed using a 7-AAD/Far-Red cytotoxicity assay against autologous tumor cells, and in vivo efficacy was evaluated in NSG mice bearing subcutaneous patient-derived tumor cell xenografts (PDCX). Results On day 14, the WIOG group showed a 1.3-fold increase in expansion compared to the control group, along with a high CD8 + /Treg ratio (454.6). Furthermore, both CD8 + and CD4 + T cells in the WIOG group exhibited elevated Granzyme B expression. RNA sequencing identified 279 upregulated genes associated with T cell activation ( CSF2, TNFRSF4 ), cytotoxicity ( IFNG, GZMB ), and anti-apoptosis ( BMF, BCL2L1 ). Compared to the controls, the WIOG group demonstrated a 1.9-fold increase in cytolytic activity in vitro and a 56% reduction in tumor growth in the patient-derived tumor cell xenograft (PDCX) model. Conclusions Taken together, we demonstrated that the addition of an agonistic GITR antibody during the early phase of TIL culture increased the CD8 + T cell to Treg cell ratio and enhanced anti-tumor T cell immunity. Enhancing TILs with a GITR agonist may be beneficial for improving the clinical outcomes of TIL-based ACT in OC.

TGF-β–driven T-cell exclusion in ovarian cancer: single-cell and spatial transcriptomic views of immune low-response states

Epithelial ovarian cancer (EOC) remains a lethal epithelial malignancy. Immune-checkpoint inhibitors have entered management for recurrent/metastatic disease; yet durable benefit is confined to a subset, reflecting TGF-β–conditioned stromal barriers and organised T-cell exclusion. In this review we summarise advances from single-cell RNA and ATAC profiling and spatial transcriptomics that resolve fibroblast, tumour and immune programmes linked to TGF-β signalling, and appraise translational opportunities spanning selective pathway modulation, checkpoint combinations and spatial biomarkers. We also discuss enduring challenges—including site-specific heterogeneity across adnexal, omental and peritoneal niches, limited assay standardisation and a scarcity of predictive metrics—that temper implementation. By integrating TGF-β–informed readouts (e.g., INHBA+ cancer-associated fibroblast burden, periostin/fibronectin indices, MHC-I status and CD8–tumour distances) with PD-1–based regimens and TGF-β-axis agents (ALK5 inhibitors, Activin A neutralisation, NOX4-directed reprogramming), emerging strategies aim to restore antigen presentation, improve lymphocyte access and remodel tumour–stroma interfaces. Our synthesis provides an appraisal of the evolving landscape of TGF-β–informed precision immuno-oncology in ovarian cancer and outlines pragmatic standards and avenues for clinical translation. We hope these insights will assist researchers and clinicians as they endeavour to implement more effective, individualised regimens.

Multi-compartment immune cell profiling highlights the prognostic relevance of CD127+ CD8+ T cells for patients with high-grade serous ovarian cancer

Ovarian cancer (OC) is a heterogeneous tumor entity with accumulated ascitic fluid in the peritoneal cavity, especially in advanced tumors. In general, a high immune cell infiltration has a favorable effect on OC patients’ outcomes. However, the composition of immune cells within the individual compartments of OC-associated locations may differ in their impact on patient prognosis. Therefore, we comprehensively investigated immune cell frequencies in matched peripheral blood, ascites, and tumor samples of 24 high-grade serous OC patients by flow cytometry and associated them with clinical parameters. Immune cell analysis demonstrated that the general immune cell infiltration was comparable between the three investigated compartments, with decreased proportions of CD8+ T cells in advanced stage OC. In addition, immune cell subsets varied significantly in their differentiation and phenotypic marker expression. In peripheral blood, classical monocytes, mature natural killer (NK) cells with cytotoxic potential (CD57+, CD16+, NKG2D+), and less differentiated T cells were more frequent. On the contrary, dendritic cells, and NKp46+ NK cells were prevalent in ascites. In OC tissues, high frequencies of immature neutrophils, CD16- NK cells, and effector memory T cells were found, although the intratumoral T cell frequency was significantly reduced compared to the two liquid samples. Additionally, T cell profiling showed high expression of one or multiple activating and inhibitory receptors in tumor samples. In particular, significant positive correlations of CD127+ CD8+ T cells among all three compartments were shown. Our results provide evidence that a higher proportion of peripheral CD127+ CD8+ T cells, which are memory T cells with low granzyme B production, was a prognostic biomarker for unfavorable progression-free survival of high-grade OC patients, independent of FIGO stage III/IV or residual tumor after surgery.

Identification of sex- and inflammation-associated heterogeneity in the mouse omentum

The omentum is a critical intraperitoneal organ essential for peritoneal homeostasis, yet detailed characterization of its cellular composition remains limited by the lack of validated markers. Here, we employed single-cell RNA sequencing to systematically define cellular heterogeneity in naive and activated mouse omentum from both sexes. Our analysis identified previously uncharacterized immune and stromal cell subsets, including three macrophage subtypes with activation-dependent gene expression patterns, implying specialized roles in inflammation and immune regulation. Comparative analysis revealed marked transcriptional differences between omental and peritoneal macrophages, underscoring tissue-specific microenvironments. Additionally, sexually dimorphic gene expression in omental stromal cells correlated with peritoneal macrophage polarization, indicating sex-specific regulatory mechanisms. Critically, macrophages from omentum of female mice with ovarian cancer metastases showed unique gene signatures associated with tumor migration and invasion. Collectively, we provide the first comprehensive atlas of omental cell populations stratified by sex and activation state, offering novel insights into peritoneal immunity and identifying potential therapeutic targets for inflammatory and metastatic diseases.

Can posttreatment blood inflammatory markers predict poor survival in gynecologic cancer?: a systematic review and meta-analysis

IntroductionPeripheral blood inflammatory markers (PBIMs) are widely used for prognostication of several malignancies, including gynecologic cancers. However, most studies do not report when PBIMs have been sampled, and the ones that do usually use pretreatment levels. Considering their potential to reflect the host immune status, posttreatment PBIMs and their dynamic changes from pretreatment levels may also carry prognostic information. A systematic review and meta-analysis were conducted to identify the prognostic value of posttreatment PBIMs and their dynamic changes from baseline in gynecologic cancers. Furthermore, among the inconsistent blood draw timing and analytical methods, we aimed to suggest the most suitable strategies in the clinical setting.MethodsFourteen eligible studies comprising 2,373 patients with cervical, ovarian, or endometrial cancer were included. The associations between survival outcomes, including overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS), and the PBIMs were extracted or estimated. The PBIMs included the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the monocyte-to-lymphocyte ratio (MLR), the systemic immune-inflammation index (SII), and the systemic inflammation response index (SIRI). Subgroup analyses examined early versus late posttreatment sampling, as well as dynamic assessments based on threshold-defined change (increase or decrease) versus simple directional change (high or low).ResultsAll PBIMs (NLR, PLR, MLR, SII, and SIRI) demonstrated significant association with relevant survival endpoints (OS, PFS, and DFS). Early sampling of within one month after treatment completion (≤ median 15 days) showed prognostic significance (pooled hazard ratios 3.43–3.55; p < 0.0001), whereas late sampling demonstrated no significant associations. Dynamic classification using specific thresholds yielded more consistent and less heterogeneous estimates than directionality-based approaches.DiscussionThis meta-analysis demonstrates the prognostic potential of posttreatment PBIMs and their dynamic change from baseline in gynecologic cancers. Sampling within one month after therapy was significantly associated with prognosis, which may reflect the importance of sampling time in relation to the different recovery times by immune cell compartments. However, considering the heterogeneity of confounders between studies, the results should be interpreted with caution. These findings warrant the need for further studies to standardize PBIM assessment in clinical practice.

Preoperative malnutrition predicts poor early immune recovery following gynecologic cancer surgery: a retrospective cohort study and risk nomogram development

BackgroundMalnutrition is prevalent in patients undergoing gynecologic cancer surgery and may compromise postoperative immune competence. However, its specific association with early immune recovery remains unclear, and validated predictive tools are lacking.MethodsThis retrospective cohort study included 1,245 women who underwent curative surgery for cervical, endometrial, or ovarian cancer between March 2021 and September 2023. Preoperative nutritional status was assessed using the Patient-Generated Subjective Global Assessment (PG-SGA), and patients were stratified into well-nourished and malnourished groups. Poor immune recovery was defined as lymphocyte count <1.0 ×109/L on postoperative day 3 (POD3). Multivariate logistic regression was used to identify independent predictors, and a nomogram was developed and internally validated using ROC analysis, calibration curve, and decision curve analysis (DCA).ResultsMalnourished patients had a significantly higher risk of poor immune recovery (36.6% vs. 16.1%, P < 0.001) and postoperative complications. In multivariate analysis, malnutrition (adjusted OR: 2.41; 95% CI: 1.82–3.22), low BMI, anemia, elevated CRP, advanced FIGO stage, open surgery, preoperative lymphopenia, and older age were independently associated with poor immune recovery. The final model demonstrated good discrimination (AUC = 0.821; 95% CI: 0.798–0.845) and clinical utility. The nomogram provides individualized risk estimates to guide perioperative immunonutrition strategies.ConclusionMalnutrition is an independent risk factor for impaired early immune recovery after gynecologic cancer surgery. Our predictive model offers a clinically applicable tool to identify high-risk patients and support personalized perioperative management. Future prospective validation is warranted.

Efficacy and safety of pembrolizumab for the treatment of advanced or recurrent ovarian cancer: a meta-analysis based on single-arm studies

ObjectiveOvarian cancer is a common malignant tumor of the female reproductive system, and traditional treatments are unsatisfactory due to its intraperitoneal spreading mechanism and its biologic characteristic of being prone to drug resistance. Pembrolizumab has demonstrated high objective remission and overall survival rates in a variety of solid tumors, and clinical trials are now available to explore its efficacy in the treatment of ovarian cancer. The objective of this systematic review and meta-analysis was to synthesize the findings of multiple clinical studies in order to evaluate the effectiveness and safety of the immunotherapeutic agent Pembrolizumab in patients diagnosed with advanced or recurrent ovarian cancer.MethodsA comprehensive search of literature published up to 19 November 2024 was conducted in the following databases: PubMed, Embase, Cochrane Library, Web of Science, Ovid_medline, Scopus, and ProQuest. The outcomes related to the administration of pembrolizumab in patients with advanced or recurrent ovarian cancer were extracted, including objective remission rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). A further meta-analysis was then performed.ResultsThis meta-analysis comprised 625 patients across nine studies. A total of 617 patients were involved in the efficacy assessment, while 592 patients were included in the safety assessment. The pooled analysis indicated an ORR of 24% (95% confidence interval [CI], 0.13–0.35), a DCR of 63% (95% CI, 0.49–0.77), a median progression-free survival (mPFS) of 4.82 months (95% CI, 3.29–6.35), and a median overall survival (mOS) of 13.54 months (95% CI, 10.35–16.73). Subgroup analysis indicated that the ORR in the PD-L1-positive group was 24% (95% CI, 0.12–0.36), while the ORR in the PD-L1-negative group was 18% (95% CI, 0.09–0.27). No statistically significant difference was observed between the two groups. The ORR was 26% (95% CI, 0.13–0.33) for patients administered a 200 mg dose every three weeks (q3w), while it was 12% (95% CI, 0.02–0.30) for those receiving a 10 mg/kg dose every two weeks (q2w). The overall incidence of adverse reactions of any grade was 81% (95% CI, 0.71–0.91), whereas the incidence of grade 3 or higher adverse reactions was 32% (95% CI, 0.09–0.54).ConclusionsThis meta-analysis indicates that pembrolizumab treatment for patients with advanced or recurrent ovarian cancer exhibits significant efficacy and an acceptable safety profile.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/ identifier CRD42024620116.

IFNγ-mediated suppression of alternative NF-κB in tumor-resident myeloid cells promotes selective recruitment of cytotoxic but not regulatory T cells

Immunotherapy is currently effective in less than half of patients with solid tumors, and most responders develop secondary progression. High infiltration of the tumor microenvironment (TME) with CD8+ cytotoxic T cells (CTLs) and low infiltration with regulatory T cells (Treg) predicts the patients’ responses to immunotherapy and long-term outcomes. To identify the mechanisms regulating long-term stability of CTL infiltration, we analyzed the impact of CTL-produced cytokines on the TME by co-culturing patient-isolated ascites cells with activated T cells. Unexpectedly, we observed that activated CTLs selectively induce cytotoxic T cell-attracting chemokines but not chemokines that attract T regulatory cells in ovarian cancer TME and tumor-associated myeloid cells, resulting in recruitment of additional CTLs without Tregs. This selectivity resulted from the unique dependence of CCL22 induction on both canonical and alternative NF-κB and the suppression of alternative NF-κB signaling by T cell-released IFNγ. Our data demonstrate that T cell-produced IFNγ suppresses alternative NF-κB signaling in TME-associated myeloid cells, allowing for the induction of CTL-attracting chemokines with the concomitant suppression of Treg-attracting CCL22. These novel functions of IFNγ and activated T cells in regulating the balance between canonical and alternative NF-κB signaling in myeloid cells provide new opportunities to enhance and stabilize the selective CTL influx in the TME.

Decoding immune low-response states in ovarian cancer: insights from single-cell and spatial transcriptomics for precision immunotherapy

Ovarian cancer represents a typically immune “cold” tumor, where obvious immunosuppression, spatial T-cell exclusion, and cellular dysfunction collectively limit immunotherapy effectiveness. Especially in high-grade serous ovarian carcinoma (HGSOC), the immune low-response state is driven by complex interactions among tumor-associated macrophages (TAMs), suppressive stromal networks, and the T-cell compartment (regulatory T cells, Tregs, and exhausted effector T cells). Emerging multi-omics technologies—particularly single-cell RNA sequencing and spatial transcriptomics—have showed the heterogeneity and spatial immune organization underlying this suppressed state. Here, we integrate these datasets to describe TAM phenotypes and spatial niches, T-cell exhaustion, Tregs accumulation, NK-cell dysfunction, and stromal barriers that enforce exclusion. We then derive phenotype-guided combination strategies to remodel the tumor microenvironment and improve responsiveness to immune checkpoint blockade. This synthesis provides a concise, multi-dimensional framework for precision immunotherapy and for overcoming resistance in immune-low ovarian cancers.

Signaling intact membrane-bound IL-15 enables potent anti-tumor activity and safety of CAR-NK cells

BackgroundChimeric antigen receptor (CAR)-NK cells are a promising and safe alternative to CAR-T cells. However, the limited persistence in vivo restricts their clinical application and sustained therapeutic responses. IL-15 has been extensively used to improve CAR-NK cell persistence and effectiveness. Nevertheless, accumulation of IL-15 might induce uncontrolled proliferation of CAR-NK cells and thus lead to fatal side-effects. Therefore, it is essential to develop a safe and effective alternative strategy to improve the persistence and anti-tumor activity of CAR-NK cells.MethodsA signaling intact membrane-bound IL-15 (mbIL-15) was designed by fusing IL-15 and full-length IL-15Rα and was systematically compared with secretory IL-15 (sIL-15) in a B7H3-targeting CAR-NK cell system regarding their functionality and safety through various in vitro and in vivo experiments.ResultsBoth expression of sIL-15 or mbIL-15 significantly enhanced the proliferation by activating STAT5 and improved anti-tumor activity of CAR-NK cells in vitro and in vivo. Although CAR-NK cells with sIL-15 quickly eliminated intraperitoneal ovarian cancer, the mice experienced severe consequences, including dysregulated CAR-NK cell expansion, intense inflammatory responses, and irreversible organ damages. In contrast, CAR-NK cells carrying mbIL-15 showed moderate cell proliferation and potent tumor killing activity without observable adverse effects in both local treatment and systemic administration models.ConclusionHead-to-head comparative studies demonstrated that signaling intact mbIL-15 significantly improved therapeutic efficacy and safety of CAR-NK cells compared to sIL-15, which provided preclinical evidence for future clinical development.

Frequency of microsatellite instability in gynecologic cancers and the efficacy of immune checkpoint inhibitors treated: real-world data from a single gynecologic center

ObjectiveThis study evaluated the incidence of Microsatellite Instability-High (MSI-H) in patients with gynecologic cancers in a single gynecologic center and investigated the effect of immune checkpoint inhibitors (ICIs) in treating MSI-H in advanced or recurrent gynecologic cancers.MethodsWe conducted a retrospective study of patients diagnosed with gynecological cancers between June 2021 and May 2024. We investigated their clinicopathological information, the results of microsatellite instability (MSI), the immunohistochemistry staining PD-L1 analyses, the molecular classification testing, and the tumor response to treatment with ICIs.ResultsAmong 1333 patients included in the analysis, the frequency of MSI-H was 1.3% (3/223) in cervical cancer, 25.7% (280/1091) in endometrial cancer, and 10.5% (2/19) in ovarian or tubal and peritoneal cancer. When the patients were evaluated by histologic type, the frequency of MSI-H was 26.1% (241/921) in endometrioid adenocarcinoma and 35.1% (20/57) in mixed adenocarcinoma. Molecular classification results for the 1020 cases that successfully underwent the tests were 71 for the POLE mutation (POLEmut) subtype, 271 for MMR-deficiency (MMRd) subtype, 571 for the non-specific molecular profile (NSMP) subtype, and 107 for the p53 abnormality (p53abn) subtype. Thirty-five patients were treated with ICIs for at least one cycle. The objective response rate (ORR) was 34.3% (95% CI, 19.1% to 52.2%). Among the patients who achieved an objective response, the median time to respond was 2.65 months, and the median duration of response had not been reached. The median progression-free survival (PFS) was 9 months (95% CI, 4 to 10), and the median overall survival (OS) had not been reached. Additionally, in the patients with endometrial cancer, the median PFS in MSI-H patients was 5 months versus 3 months in microsatellite stable (MSS) patients (Δ = 2 months; p=0.92), and the median OS in both MSI-H and MSS patients had not been reached (p=0.89).ConclusionThis study had shown the MSI-H frequencies for the three major types of gynecological tumors and demonstrated the clinical benefit of treatment with ICIs in patients with advanced or recurrent gynecologic cancer. Among endometrial cancer patients, the effects of immunotherapy may be consistent regardless of MSI status.

Hybrid regulatory T cells: camouflaged architects of tumor immunity

Distinct from conventional Foxp3+ regulatory T cells (Tregs), T-bet+ Tregs represent a stable subset of immunosuppressive T cells characterized by co-expression of the transcription factors (TFs) Foxp3 and T-bet. Given that Tregs were also reported to co-express Foxp3 together with effector T cell TFs such as GATA3, or RORγt, we propose the term hybrid Tregs (hTregs) to distinguish between these Tregs that co-express Foxp3 together with effector T cell TFs from conventional Foxp3+ Tregs. Therefore, this review will focus on hTreg cells, a specific subset of CD4+ T cells, and discuss the different types of hTregs with particular emphasis on T-bet+ hTregs. T-bet+ hTregs exhibit unique features including IFN-γ production, high expression of immune checkpoints (PD-1, CTLA-4, GITR, OX40, TIGIT), and chemokine receptors (CXCR3, CCR5). Through secretion of IL-10, TGF-β and IFN-γ, T-bet+ hTregs modulate both innate and adaptive immune responses within the tumor microenvironment (TME). Their high expression of CD73 contributes to adenosine-mediated immunosuppression, while CXCR3 and CCR5 facilitate their recruitment to inflammatory sites. T-bet+ hTregs were reported to accumulate in multiple human cancers, including lung, ovarian, and colorectal carcinomas. Despite these advancements, the function of hTregs in diseases such as cancer remains poorly understood, and requires further investigations. For instance, some studies suggest T-bet+ hTregs to be anti-inflammatory due to their production of IL-10, TGF-β, and superior suppressive capacity compared to conventional Tregs. Yet, other studies have reported that T-bet+ hTregs exhibit enhanced proinflammatory functions in colitis and other pathologies. We will then highlight current known mechanisms that promote the differentiation and functions of T-bet+ hTregs in cancer. Lastly, we will discuss the advancements and opportunities for therapeutic targeting of T-bet+ hTregs in cancer immunotherapy.

Integrated multiomics characterization reveals cuproptosis-related hub genes for predicting the prognosis and clinical efficacy of ovarian cancer

BackgroundAs a prevalent malignancy in women, ovarian cancer (OC) presents a challenge in clinical practice because of its poor prognosis and poor therapeutic efficacy. The mechanism by which cuproptosis activity is accompanied by immune infiltration in OC remains unknown. Here, we investigated cuproptosis-related OC subtypes and relevant immune landscapes to develop a risk score (RS) model for survival prediction.MethodsCuproptosis-related genes (CRGs) were identified to construct molecular subtypes via an unsupervised clustering algorithm based on the expression profiles of survival-related CRGs in the GEO database. Single-cell datasets were used to estimate immune infiltration among subtypes. The RS oriented from molecular subtypes was developed via LASSO Cox regression in the TCGA OC dataset and independently validated in the GEO and TCGA datasets. Hub markers from RS were identified in tissues and cell lines. The function of the key gene from RS was identified in vitro.ResultsWe investigated cuproptosis activity and immune infiltration to establish three clinical subtypes of OC based the differentially expressed genes (DEGs) from CRGs to create an RS model validated for clinical efficacy and prognosis. Six hub genes from the RS served as ongenic markers in OC tissues and cell lines. The function of GAS1 in the RS model revealed that it exerts oncogenic effects.ConclusionsOur study provides a novel RS model including 6 hub genes associated with cuproptosis and immune infiltration to predict OC prognosis as well as clinical efficacy.

Advance in therapies targeting tumor-associated macrophages in ovarian cancer

Ovarian cancer remains the deadliest gynecologic malignancy, with its aggressive progression and therapeutic resistance heavily influenced by the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), the predominant immune infiltrates in OC, play pivotal roles in metastasis, immunosuppression, and chemoresistance by adopting a pro-tumoral M2 phenotype. Despite promising preclinical results, clinical translation faces challenges, such as on-target toxicity and incomplete understanding of TAM ontogeny in humans. This review summarizes the origins, heterogeneity, and functional plasticity of TAMs, emphasizing their mechanistic contributions to OC progression through epithelial-mesenchymal transition (EMT), angiogenesis, and immune evasion. We outline the emerging evidence that TAMs drive platinum resistance via exosomal signaling and metabolic reprogramming, underscoring TAMs as central mediators of OC pathogenesis and treatment paradigms.

Multi-omics analysis and experiments uncover the link between cancer intrinsic drivers, stemness, and immunotherapy in ovarian cancer with validation in a pan-cancer census

BackgroundAlthough immune checkpoint inhibitors (ICIs) represent a substantial breakthrough in cancer treatment, it is crucial to acknowledge that their efficacy is limited to a subset of patients. The heterogeneity and stemness of cancer render its response to immunotherapy variable, warranting the identification of robust biomarkers for evaluation.MethodsPublicly available Ovarian Cancer (OV) single-cell RNA (scRNA) sequence dataset was collected and analyzed to elucidate the intrinsic driver gene of OV cancer cells. Through genome-scale CRISPR screening of RNA sequencing data from Project Achilles, essential genes specific to OV were identified. A novel cancer stem cell index (CSCI) was developed and validated using multiple advanced algorithms and large-scale datasets, as well as corresponding clinical features, including 14 OV transcriptomic datasets, 7 pan-cancer ICI transcriptomic cohorts and one melanoma scRNA dataset derived from PD-1 treated patients.ResultsChromosomal 20q gain, 8q gain, and 5q loss have been identified as ovarian cancer-specific driving variations. By analyzing large-scale datasets of ovarian cancer transcriptomics, including scRNA and CRISPR cell line datasets, we have identified a gene set that influences tumor intrinsic drivers and stemness properties. We then developed the CSCI to predict the prognosis and response to immunotherapy in ovarian cancer patients using advanced machine learning algorithms. When applied to PD1/PD-L1 ICI transcriptomic cohorts, CSCI consistently and accurately predicts tumor progression and immunotherapy benefits, with a mean AUC greater than 0.8. Notably, compared to previously established signatures, CSCI demonstrates better predictive performance across multiple ovarian cancer datasets. Intriguingly, we discovered that amplification of CSE1L enhances the stemness of tumor-initiating cells, facilitates angiogenesis, and the formation of ovarian cancer, which can serve as a potential therapeutic target. Finally, experiments validated that CSE1L promotes progression, migration, and proliferation of ovarian cancer.ConclusionsOur study has uncovered a robust correlation between variations in cancer intrinsic drivers and stemness, as well as resistance to immunotherapy. This finding provides valuable insights for potential strategies to overcome immune resistance by targeting genes associated with stemness.

Research trends and hotspots in the tumor microenvironment of ovarian cancer: a bibliometrics and visualization study from 2005 to 2024

BackgroundThe tumor microenvironment (TME) is crucial in influencing the progression and therapeutic response of ovarian cancer.MethodThis study conducted a comprehensive bibliometric and visualization analysis of research trends and focal areas concerning the ovarian cancer microenvironment from 2005 to 2024. A total of 1,720 pertinent articles were identified from the Web of Science Core Collection (WoSCC) database.ResultsThe analysis revealed a notable increase in research activity on the TME of ovarian cancer, particularly during the period from 2019 to 2022. The United States and China were the most active countries in this field, and the University of Texas System was the scientific research institution with the largest number of articles. Cancer Research and Clinical Cancer Research were the most cited journals. Weiping Zou and Anil K Sood were recognized as the most cited researchers. The study systematically identified key research hotspots within this field, encompassing immune checkpoint inhibitors, single-cell RNA sequencing technology, the TME heterogeneity, the TGFβ signaling pathway, and the impact of PARP inhibitors on the tumor immune microenvironment (TIME).ConclusionThis study provides a valuable reference for the evolution and prospective directions of TME research in ovarian cancer, underscoring the critical importance of a comprehensive understanding of the TME to enhance treatment strategies for ovarian cancer.

Integrated analysis of single-cell and bulk transcriptomics reveals the prognostic value and underlying mechanisms of crotonylation in ovarian cancer

BackgroundOvarian cancer remains the deadliest gynecological malignancy with 5-year survival rates below 40% due to frequent recurrence and chemoresistance. Aberrant crotonylation, a type of epigenetic modification, has been implicated in the proliferation, metastasis, and immune evasion of various cancers. However, its role in the ovarian cancer microenvironment and clinical outcomes remains unexplored. The aim of this study was to develop a prognostic model for ovarian cancer on the basis of crotonylation and to investigate the underlying mechanisms and potential of crotonylation for targeted therapy.MethodsWe systematically analyzed single-cell RNA-seq and bulk transcriptomic datasets from ovarian cancer patients. Cellular crotonylation activity was quantified using AUCell algorithm. Potential prognostic genes were identified through DEG analysis and Weighted gene correlation network analysis (WGCNA), and the associated molecular mechanisms were elucidated via Gene set enrichment analysis (GSEA). An ovarian cancer prognosis model were constructed by integrating machine learning algorithms. Immune microenvironment features were assessed using CIBERSORT, ESTIMATE and TIDE algorithms, with drug sensitivity predicted via genomics of drug sensitivity in cancer.ResultsThe ovarian cancer microenvironment is characterized by abundant immune cell infiltration, with significant differences in crotonylation levels among 7 cell subtypes. We identified 451 key crotonylation-related genes. The crotonylation risk score (RS) model demonstrated robust prognostic performance. High-RS groups showed immunosuppressive characteristics: decreased follicular helper T cells and activated NK cells, concomitant with M2 macrophage enrichment. Elevated RS was associated with increased stromal activation, as indicated by a higher ESTIMATE score, and enhanced immune evasion potential, reflected by an elevated TIDE score. Notably, high-RS patients exhibited upregulated PDL1 and CD40, suggesting increased immunotherapy susceptibility. Pharmacogenomic analysis identified vinblastine with differential sensitivity, providing actionable targets for RS-stratified therapy.ConclusionWe elucidated the significant impact of crotonylation on the ovarian cancer microenvironment and prognosis. We developed and validated a novel prognostic model for ovarian cancer that can serve as a tool for predicting patient outcomes and characterizing the immune microenvironment. These findings enhance our understanding of the role of crotonylation in ovarian cancer and establish a robust framework for developing therapeutic strategies targeting crotonylation.

Analysis of m7G-related signatures in the tumor immune microenvironment and identification of clinical prognostic regulators in ovarian cancer

Ovarian cancer (OV) is the most lethal gynecological malignancy in the world. At present, the effect of m7G modification-related genes on the development of ovarian cancer remains unclear. We performed consensus clustering of ovarian cancer samples based on the expression of 24 m7G modification-related genes, and obtained 2 subtypes. There were some differences in immune cell infiltration between the two subtypes. Furthermore, enrichment analysis showed that differential genes were mainly enriched in several pathways and biological processes, including positive translation regulation and TRAPP complex. Multivariate cox regression analysis confirmed two genes (DCP2 and NUDT16) related to prognosis for the construction of risk score prediction models. The risk map of survival status showed that the high-risk samples had a shorter survival time (p<0.05). Risk score was an independent prognostic factor for OV and correlated with immunotherapy response. We also performed network analysis for DCP2 and NUDT16. We further explored the effects of the genes on cellular function and prognosis. In conclusion, this study provided a new perspective for the development mechanism of ovarian cancer.

PD-1 and LAG-3 were optimal combination of immune checkpoints for predicting poor clinical outcomes of patients with ovarian cancer

BackgroundAlthough immune checkpoint blockade (ICB) therapy has transformed the therapeutic landscape for ovarian cancer (OC), the predictive utility of immune checkpoint (IC) expression signatures in stratifying clinical outcomes requires further systematic interrogation.MethodsTranscriptomic profiles from 147 OC patients within The Cancer Genome Atlas (TCGA) cohort were interrogated to assess the prognostic significance of ICs. These genomic findings were subsequently validated through immunohistochemical analysis of an independent institutional cohort comprising 74 OC tissue specimens.ResultsBoth TCGA and validation cohorts demonstrated that elevated expression of PD-1 and LAG-3 correlated with inferior overall survival (OS) in patients with OC. Importantly, among the ICs, PD-1/LAG-3 co-expression emerged as the optimal combinatorial biomarker, independently predicting adverse outcomes [hazard ratio (HR) = 1.74, 95% confidence interval (CI): 1.12-2.70, P < 0.001]. The derived nomogram model incorporating PD-1/LAG3 status, TNM stage, histologic grade, and age generated patient-tailored 1–5 year OS rate estimates. Notably, risk stratification using this model significantly enhanced prognostic precision versus conventional parameters (TNM stage or histologic grade) alone, especially in patients with serous cystadenocarcinoma.ConclusionElevated IC expression correlated with poor OS in OC patients. Specifically, PD-1/LAG-3 co-expression emerged as the optimal prognostic biomarker pair, representing a promising therapeutic target for dual checkpoint blockade strategies in OC.

Integrative single-cell and exosomal multi-omics uncovers SCNN1A and EFNA1 as non-invasive biomarkers and drivers of ovarian cancer metastasis

BackgroundOvarian cancer (OV) is the deadliest gynecologic malignancy owing to its late diagnosis and high metastatic propensity. Current biomarkers lack sufficient sensitivity and specificity for the detection of early-stage cancer. To address this gap, we integrated single‐cell transcriptomic profiling of tumor tissues with analysis of circulating exosomal RNA, aiming to uncover candidate markers that reflect tumor heterogeneity and metastatic potential and that may serve as sensitive, non‐invasive diagnostics.MethodsWe integrated single-cell RNA sequencing (scRNA-seq) data from primary tumors and metastatic lesions with bulk tissue transcriptomes and plasma-derived exosomal RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) shared across tumor cells, metastatic subpopulations, and exosomes were identified through intersection analysis. Candidate genes were validated in clinical specimens using qPCR and immunohistochemistry. We then applied ten machine learning algorithm to exosomal transcriptomic data to evaluate diagnostic performance and identify the optimal classifier. Tumor cell differentiation states were evaluated using CytoTRACE, and intercellular communication was analyzed with CellChat.ResultsIntersection analysis highlighted 52 overlapping DEGs, of which SCNN1A and EFNA1 emerged as the top prognostic indicators. Both genes were significantly upregulated in tumor tissues, metastatic foci, and plasma exosomes (P < 0.01). The exosome-based Adaboost model had an area under the curve of 0.955 in an independent test cohort. Single-cell subcluster analyses revealed high SCNN1A/EFNA1 expression correlated with stem-like differentiation states and enriched pathways associated with immune evasion and adhesion. CellChat analysis demonstrated that highly differentiated tumor cells extensively engaged with fibroblasts and endothelial cells, implying their role in niche formation.ConclusionsBy coupling single-cell, bulk tissue, and exosomal transcriptomics, we elucidated the key molecular drivers of OV metastasis and established SCNN1A and EFNA1 as promising non-invasive biomarkers. This multi-omics framework provides an effective strategy for early detection and a better understanding of metastatic progression in OV.

Pan-cancer analysis of phagocytosis regulators in female-specific cancers: a focus on HMGB2

IntroductionTumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment, regulating immune escape and promoting cancer progression. Understanding the role of phagocytosis regulators in female-specific cancers is essential for developing effective therapeutic strategies.MethodsWe performed comprehensive analyses of public databases to evaluate the expression, somatic mutations, and copy number variations of phagocytosis regulators. DNA methylation patterns, biological pathways, survival outcomes, and drug sensitivity were assessed. Additionally, immune modulators, immune cell infiltration, and single-cell sequencing were used to explore alterations in phagocytosis and their cellular origins. The functional role of HMGB2 in tumor cell behavior was validated through in vitro assays.ResultsPhagocytosis regulators exhibited differential expression across various female-specific cancers, with key genes such as CD47 and FOXO1 playing significant roles in modulating tumor progression. High-frequency mutations were found in PTEN, ARID1A, and UBR4. Genes like COX5B and MS4A1 emerged as potential predictors of clinical outcomes and therapeutic response. HMGB2 knockdown significantly inhibited cancer cell proliferation, migration, and invasion in female-specific cancers. HMGB2 knockdown in macrophages led to a significant impairment in phagocytosis of breast, cervical, ovarian, and endometrial cancer cells. Furthermore, when HMGB2 knockdown was combined with Palbociclib treatment, a significant decrease in tumor cell proliferation was observed across multiple cancer models.ConclusionThis study highlights the pivotal role of phagocytosis regulators, particularly HMGB2, in the progression of female-specific cancers. Targeting HMGB2 offers promising therapeutic opportunities, potentially enhancing precision oncology and improving patient outcomes.

Transglutaminase 2 regulates ovarian cancer metastasis by modulating the immune microenvironment

IntroductionOvarian cancer is the most lethal gynecological malignancy. Deepening our knowledge of the interactions within the tumor microenvironment (TME) is important for discovering new targeted treatment strategies. Transglutaminase 2 (TG2) is a protein implicated in many biological and pathophysiological processes, including promoting tumor progression in ovarian cancer. Its role in disease progression has been studied in ovarian cancer cells; however, its role in the ovarian TME is less understood.MethodsIn this study, for the first time, we assessed the therapeutic potential of novel covalent irreversible small molecule TG2 inhibitors in xenograft models of ovarian cancer. We further elucidated the role of TG2 in ovarian cancer cells and syngeneic tumors by immune phenotyping using flow cytometry, RNA sequencing, and immunohistochemistry to characterize the contribution of TG2 in the TME to the metastatic process of ovarian cancer.ResultsTo investigate the transamidation catalytic and GTP binding activities of TG2 in cancer cells, we used several TG2 inhibitors, some of which decreased invasiveness of human ovarian cancer cell lines in vitro and lengthened survival of the SKOV3 xenograft model. Using the ID8 Trp53-/- Brca1-/- and KPCA.B syngeneic mouse models of ovarian cancer, we defined the contribution of TG2 in the TME to the metastatic process. Lack of TG2 in the TME prolonged survival in the ID8 Trp53-/- Brca1-/- metastatic model, but it did not affect survival in the non-metastatic KPCA.B model. Through extensive analysis of the immune composition in both the primary tumor and metastatic ascites in the ID8 Trp53-/- Brca1-/- model, we discovered that the lack of host TG2 resulted in decreased frequency of immunosuppressive tumor-associated macrophages, and increased frequency of T cells, NK cells, and B cells. RNA sequencing of the primary tumors with or without TG2 present in the TME, revealed an enrichment of pathways related to B cell activation and regulation.DiscussionThese findings highlight the importance of TG2 in the TME for ovarian cancer metastasis, potentially by activation of humoral immunity and specifically highlight a crucial role for TG2 in modulating B cells to prolong survival in mouse models of ovarian cancer.

Spotlight on nuclear PD-L1 in ovarian cancer chemoresistance: hidden but mighty

IntroductionOvarian cancer (OVCA) has a five-year survival rate of approximately 45%, with little improvement over recent decades. Although anti-PD-L1 therapies have shown substantial efficacy in other solid tumors, their effectiveness in OVCA has been limited. These treatments target only membranous and soluble forms of PD-L1, without addressing nuclear-localized PD-L1. The role of nuclear PD-L1 in OVCA chemoresistance, however, remains largely unexplored. In this study, we examined the prognostic significance of nuclear PD-L1 and its interactions with plasma gelsolin (pGSN) and CD8+ T cells within the tumor microenvironment.MethodsUsing immunofluorescence, we quantified nuclear PD-L1, pGSN, and additional markers in OVCA samples. Statistical analyses and machine learning approaches were employed to assess associations between marker expression, patient outcomes, and chemoresistance.ResultsIncreased nuclear PD-L1 was associated with disease recurrence, chemoresistance and poor overall survival. Although CD8+ T cells provided survival benefits to patients, elevated PD-L1 hindered these benefits resulting in shortened disease free (DFS) and overall survival (OS). Co-expression of PD-L1 and pGSN was also associated with shortened DFS, OS and chemoresistance.DiscussionThese findings indicate that nuclear PD-L1 serves as a poor prognostic marker in OVCA, being associated with tumor recurrence, chemoresistance, and reduced overall survival. Targeting nuclear PD-L1 may represent a novel therapeutic strategy to improve outcomes in patients with OVCA.

Tumor-restricted activation of Vγ9Vδ2 T cells via bispecific Evobodies: a novel strategy for safe and potent immunotherapy in ovarian cancer

Introduction Vγ9Vδ2 T cells have been clinically evaluated—both in vivo and ex vivo —for their efficacy against solid tumors over several decades. Although recent therapeutic approaches have renewed hope, significant and reproducible benefits for patients with solid tumors remains to be demonstrated. Material & Methods We have developed bispecific biologics in an IgG-extended format that bind both to Folate Receptor alpha (FOLR1), which is highly expressed in the majority of ovarian cancers, and to the activating butyrophilin (BTN)3A. By reducing the affinity of the BTN3A agonist and leveraging the increased avidity of the tetravalent, bispecific antibody, activation of BTN3A is restricted to FOLR1-positive tumors, thereby avoiding off-target activation of non-tumor cells. Results Using RTCA co-culture assays with Vγ9Vδ2 T cells and tumor cell lines, we identified “Evobodies” that exhibit a strong therapeutic window and high potency against FOLR1-positive cells, while sparing healthy, FOLR1-negative tissue. Moreover, the lead molecule demonstrates high efficacy in a human autologous, patient-derived ex vivo tumor tissue model at unaltered/physiological effector-to-target (E:T) ratios. Importantly, we show that our tumor-engaging molecules avoid premature immune cell activation, degranulation, and cytokine release in the absence of FOLR1-positive tumor cells. They likely establish a cytokine gradient from the tumor site, harnessing the full potential of the natural local anti-infection response to target cancer cells. Discussion Thus, Evobodies represent a novel, first-in class of biologics for solid tumor treatment and are well-suited for further clinical development.

Immunosuppressive mechanisms and therapeutic targeting of regulatory T cells in ovarian cancer

Ovarian cancer remains the most lethal gynecologic malignancy, largely due to its late-stage diagnosis and immunosuppressive tumor microenvironment (TME). A key mediator of immune evasion in ovarian cancer is the infiltration and activation of regulatory T cells (Tregs), which suppress antitumor immunity and foster therapeutic resistance. Emerging therapeutic strategies to target Tregs—such as cytokine modulation, checkpoint blockade, metabolic inhibitors, and epigenetic regulators—are critically evaluated for their potential to restore antitumor immunity. This review synthesizes recent advances in understanding how the ovarian TME shapes Treg biology, highlighting mechanisms such as cytokine signaling, chemokine-driven recruitment, metabolic reprogramming, and immune checkpoint interactions, as well as the phenotypic and functional heterogeneity of tumor-infiltrating Tregs, including tissue-resident and follicular subsets, and their clonal expansion in response to tumor antigens. By elucidating the dynamic crosstalk between Tregs and the ovarian TME, this review provides a framework for developing novel immunotherapies to overcome Treg-mediated immunosuppression and improve clinical outcomes.

Unveiling drug resistance pathways in high-grade serous ovarian cancer(HGSOC): recent advances and future perspectives

High-Grade Serous Ovarian Carcinoma (HGSOC) represents the most prevalent and lethal subtype of ovarian cancer, with approximately 225,000 new cases reported globally each year and a five-year survival rate of merely 49.1%. The clinical management of HGSOC encounters substantial challenges, primarily attributable to its intricate drug resistance mechanisms, which involve multiple biological processes, including tumor cell heterogeneity, microenvironment remodeling, gene mutations, and drug efflux. This study systematically reviews the most recent advancements in HGSOC drug resistance research, concentrating on the molecular biological foundations of resistance mechanisms, innovative detection strategies, and potential therapeutic approaches. The research indicates that HGSOC drug resistance constitutes a complex process characterized by multifactorial interactions, involving aberrant cell signaling pathways, dynamic alterations in the tumor microenvironment, and specific expressions of molecular markers. In this review, we systematically analyzed and investigated the intricate biological behaviors associated with HGSOC drug resistance, which not only enhances the understanding of disease progression but also provides essential theoretical foundations for the development of more precise and effective targeted therapies. This review firstly illustrated the detailed drug resistance cellular and molecular mechanisms underlying HGSOC chemotherapy, which can pave the way for future studies in HGSOC drug resistance practices.

Crosstalk between stromal, immune, and ovarian cancer cells in lipid-rich tumor microenvironment exhibits proliferative features

Lipid metabolism reprogramming has long been noticed as the hallmark of ovarian cancer, in order to maintain proliferative features including rapid cell division, metastasis capability, and chemotherapy resistance, as well as to survive under environmental stress, alteration of lipid metabolic pathways takes place, especially over-expression of rate-limiting enzymes, enhances lipid uptake, fatty acid synthesis, β-oxidation, lipid storage, and cellular membrane construction. In lipid-rich ascites and omental tumor microenvironments, the biological functions of stromal and immune cells change, forming a premetastatic niche and immunosuppressive tumor microenvironment via modifying extracellular matrix components and secreting cytokines. The crosstalk between stromal, immune, and ovarian cancer cells results in tumor proliferation, metastasis, and escape of immune surveillance. Given the importance of lipid metabolism for ovarian cancer survival, targeting lipid metabolism key enzymes in ovarian cancer or stromal tumor microenvironment may bring novel insights for ovarian cancer treatment.

The role of notch signaling pathway in cancer: mechanistic insights, therapeutic potential, and clinical progress

This article presents a comprehensive literature review on the role of the Notch signaling pathway in cancer and its molecular mechanisms. The Notch signaling pathway plays an important role in various types of cancer by regulating key biological processes such as epithelial-endothelial transition, angiogenesis, apoptosis and metabolic reprogramming. This article reviews the relevant mechanisms of the Notch signaling pathway in colorectal cancer, ovarian cancer, oral squamous cell carcinoma, gastric cancer and chronic lymphocytic leukemia, highlighting its dual roles in promoting tumor growth, inhibiting tumor progression and potential therapeutic applications in oncology. Meanwhile, the key roles of the Notch signaling pathway in regulating tumor drug resistance and shaping the tumor microenvironment are discussed, highlighting its importance in clinical applications. Through this review, some ideas and hints for future research directions can be provided to the readers of Notch pathway related research.

Case Report: Activated PI3-kinase-δ syndrome and ovarian malignancies: a case series from the European ESID-APDS registry

Activated phosphoinositide-3-kinase-delta (PI3Kδ) syndrome (APDS) is an autosomal dominant inborn error of immunity (IEI) characterized by combined immunodeficiency and immune dysregulation with increased risk for lymphoma and other non-lymphoid malignancies. We describe five patients with ovarian malignancies among 110 female APDS patients participating in the European Society for Immunodeficiencies (ESID) registry and identified three additional cases in the literature. These findings document a relevant predisposition to these non-hematological malignancies in APDS patients.

Association between protein diet score and colorectal adenomas risk: a prospective study

Objective Given the significantly increased risk of colorectal adenoma in middle-aged and elderly populations, identifying modifiable risk factors remains a priority. While dietary protein is an essential nutrient in human metabolism, its relationship with colorectal adenoma remains controversial. With advances in nutritional science, contemporary dietary guidelines advocate increasing plant-based protein intake to achieve a more balanced protein consumption pattern. To provide new insights, we sought to investigate the association between colorectal adenoma risk and the Protein Diet Score, which comprehensively evaluates both protein intake and sources. Methods This analysis was based on data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The Cox proportional hazards regression model was utilized to compute the hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic spline was employed to illustrate the variation in colorectal adenoma risk across the entire spectrum of the Protein Diet Score. Additionally, subgroup analyses were conducted to ascertain possible effect modifiers, and several sensitivity analyses were performed to evaluate the robustness of the findings. Results During the mean follow-up period of 11.0 years, 992 newly diagnosed colorectal adenomas were identified. In the fully adjustment for potential confounders, the inverse association between Protein Diet Score and colorectal adenoma risk remained statistically significant with an HR of 0.81 (95% CI: 0.67-0.99; P trend =0.005) comparing the highest versus lowest quartile. Restricted cubic spline analysis revealed a linear inverse relationship between Protein Diet Score and colorectal adenoma risk (P for nonlinearity =0.317). In the subgroup analyses, we observed a more pronounced inverse association between Protein Diet Score and colorectal adenoma among participants with a history of hypertension (HR Quartile 4 vs. Quartile 1 : 0.60; 95% CI: 0.43-0.85; P interaction =0.017). Finally, a series of sensitivity analyses strengthened the robustness of our findings. Conclusion Our findings indicate that higher Protein Diet Score is associated with reduced colorectal adenoma incidence among middle-aged and elderly Americans, with similar findings observed for the PAR. These results provide important evidence for optimizing protein intake and source composition to promote intestinal health.

Structural and functional characterization of IgG- and non-IgG-based T-cell-engaging bispecific antibodies

Bispecific T-cell-engaging antibodies are a growing class of therapeutics with numerous molecules being tested in clinical trials and, currently, seven of them have received market approval. They are structurally complex and function as adaptors to redirect the cytotoxicity of T cells to kill tumor cells. T-cell-engaging bispecific antibodies can be generally divided into two categories: IgG/IgG-like and non-IgG-like formats. Different formats may have different intrinsic potencies and physiochemical properties, and comprehensive studies are needed to gain a better understanding of how the differences in formats impact on structural and functional characteristics. In this study, we designed and generated bispecific T-cell-engaging antibodies with IgG-like (DVD-Ig) and non-IgG (BiTE) formats. Both target the same pair of antigens (EGFR and CD3) to minimize the possible influence of targets on functional characterization. We performed a side-by-side comparison to assess differences in the physiochemical and biological properties of these two bispecific T-cell-engaging antibodies using a variety of breast and ovarian cancer cell-based functional assays to delineate the structural–functional relationships and anti-tumor activities/potency. We found that the Fc portion of T-cell-engaging bispecific antibodies can significantly impact antigen binding activity, potency, and stability in addition to eliciting different mechanisms of action that contribute the killing of cancer cells.

Advancements in ovarian cancer immunodiagnostics and therapeutics via phage display technology

Ovarian cancer, ranking as the seventh most prevalent malignancy among women globally, faces significant challenges in diagnosis and therapeutic intervention. The difficulties in early detection are amplified by the limitations and inefficacies inherent in current screening methodologies, highlighting a pressing need for more efficacious diagnostic and treatment strategies. Phage display technology emerges as a pivotal innovation in this context, utilizing extensive phage-peptide libraries to identify ligands with specificity for cancer cell markers, thus enabling precision-targeted therapeutic strategies. This technology promises a paradigm shift in ovarian cancer management, concentrating on targeted drug delivery systems to improve treatment accuracy and efficacy while minimizing adverse effects. Through a meticulous review, this paper evaluates the revolutionary potential of phage display in enhancing ovarian cancer therapy, representing a significant advancement in combating this challenging disease. Phage display technology is heralded as an essential instrument for developing effective immunodiagnostic and therapeutic approaches in ovarian cancer, facilitating early detection, precision-targeted medication, and the implementation of customized treatment plans.

Integration of scRNA-seq and bulk RNA-seq to reveal the association and potential molecular mechanisms of metabolic reprogramming regulated by lactylation and chemotherapy resistance in ovarian cancer

ObjectiveOvarian cancer (OC) ranks among the foremost causes of mortality in gynecological malignancies, with chemoresistance being the primary factor contributing to unfavorable prognosis. This work seeks to clarify the mechanisms of resistance-related lactylation in OC, intending to offer novel theoretical foundations and therapy strategies for addressing chemoresistance.MethodsThrough the combined analysis of bulk RNA-seq and single-cell RNA-seq data, we initially found lactylation genes linked to chemoresistance. Subsequently, we employed differential expression analysis, survival analysis, enrichment analysis, and other methodologies to further investigate the roles and molecular mechanisms of these genes in tumor resistance. Ultimately, we investigated the differential expression of these genes in resistant and non-resistant tissues and cells via experimentation.ResultsWe found two candidate genes associated with lactylation chemoresistance, ALDH1A1 and S100A4. Analysis of single-cell data indicated that tumor cells represent the primary cell subpopulation relevant to resistance studies. Subpopulation analysis indicated that several tumor cell subtypes were markedly linked to resistance, with elevated expression levels of ALDH1A1 and S100A4 in the resistant subpopulation, notably correlating with various immunological and metabolic pathways. Analysis of metabolic pathways indicated that oxidative phosphorylation and glycolysis activity was elevated in the resistant subpopulation, and lactic acid buildup was associated with chemoresistance. The investigation of the marker gene protein-protein interaction network in the resistant subgroup elucidated the intricate interactions among these genes. The expression levels of ALDH1A1 and S100A4 in the OC tissues of the platinum-resistant cohort were markedly elevated compared to the sensitive cohort, with a considerable rise in S100A4 expression observed in resistant OC cells, demonstrating co-localization with lactylation.ConclusionThis work elucidates the significant function of lactylation in OC chemoresistance and identifies ALDH1A1 and S100A4 as possible genes associated with drug resistance. These findings enhance our comprehension of the mechanisms behind chemoresistance in OC and offer critical insights for the formulation of novel therapeutic options.

GNA15 predicts poor outcomes as a novel biomarker related to M2 macrophage infiltration in ovarian cancer

BackgroundThe exploration of genetic signatures within the ovarian cancer (OC) tumor microenvironment (TME) remains limited. M2-like tumor-associated macrophages (M2-like TAMs) are pivotal in OC progression and therapy. This study aims to establish a novel prognostic signature and identify M2-like TAM-related biomarkers in OC using RNAseq-based transcriptome analysis.MethodsPrognostic M2-like TAM-related genes were identified through univariate Cox regression, consensus clustering, and LASSO regression. Immune landscape analysis was conducted to assess immune cell composition and immune checkpoint genes in high- and low-risk groups. Subsequently, in vitro cell experiments and OC cohorts were performed.ResultsGene set enrichment analysis revealed that GNA15 is involved in immune responses like leukocyte transendothelial migration and FcγR-mediated phagocytosis. GNA15 was up-regulated in cisplatin-resistant OC cells, and its in vitro down-regulation decreased cell proliferation. An eight-gene prognostic model, including M2-like TAM-related genes, independently predicted poor outcomes in OC. GNA15 emerged as a hub gene positively correlated with M2-like TAMs infiltration, predicting unfavorable outcomes across OC cohorts. Moreover, GNA15 expression correlated positively with CD163 expression, suggesting its role in macrophage polarization.ConclusionGNA15 plays an immunosuppressive role in OC progression linked to M2-like TAMs polarization and stands as a potential prognostic marker in OC.

cGAS/STING signaling pathway in gynecological malignancies: From molecular mechanisms to therapeutic values

Gynecological cancers, including cervical, ovarian, and endometrial malignancies, remain a significant global health burden, exacerbated by disparities in access to preventive measures such as HPV vaccination and routine screening. The cGAS/STING signaling pathway, a pivotal mechanism in innate immunity, detects cytosolic DNA from pathogens or cellular damage, triggering immune responses via type I interferons and inflammatory cytokines. This pathway’s dual role in gynecological cancers, either promoting antitumor immunity or facilitating tumor immune evasion, makes it a compelling target for innovative therapies. The article outlines cGAS/STING’s influence on tumor microenvironments, immune surveillance, and inflammation, with emphasis on molecular mechanisms driving cancer progression. It explores interactions between DNA damage response pathways and immune modulation, highlighting the impact of cGAS/STING activation or suppression in ovarian, cervical, and endometrial cancers. The therapeutic potential of STING agonists, PARP inhibitors, and targeted immunotherapies is reviewed, demonstrating how these approaches can boost immune responses, counteract chemotherapy resistance, and improve patient outcomes. The study also discusses strategies for leveraging cGAS/STING signaling to enhance the efficacy of immunotherapies and address tumor-mediated immune suppression, providing insights into future directions for personalized cancer treatments.

Characterizing tumor biology and immune microenvironment in high-grade serous ovarian cancer via single-cell RNA sequencing: insights for targeted and personalized immunotherapy strategies

BackgroundHigh-grade serous ovarian cancer (HGSOC), the predominant subtype of epithelial ovarian cancer, is frequently diagnosed at an advanced stage due to its nonspecific early symptoms. Despite standard treatments, including cytoreductive surgery and platinum-based chemotherapy, significant improvements in survival have been limited. Understanding the molecular mechanisms, immune landscape, and drug sensitivity of HGSOC is crucial for developing more effective and personalized therapies. This study integrates insights from cancer immunology, molecular profiling, and drug sensitivity analysis to identify novel therapeutic targets and improve treatment outcomes. Utilizing single-cell RNA sequencing (scRNA-seq), the study systematically examines tumor heterogeneity and immune microenvironment, focusing on biomarkers influencing drug response and immune activity, aiming to enhance patient outcomes and quality of life.MethodsscRNA-seq data was obtained from the GEO database in this study. Differential gene expression was analyzed using gene ontology and gene set enrichment methods. InferCNV identified malignant epithelial cells, while Monocle, Cytotrace, and Slingshot software inferred subtype differentiation trajectories. The CellChat software package predicted cellular communication between malignant cell subtypes and other cells, while pySCENIC analysis was utilized to identify transcription factor regulatory networks within malignant cell subtypes. Finally, the analysis results were validated through functional experiments, and a prognostic model was developed to assess prognosis, immune infiltration, and drug sensitivity across various risk groups.ResultsThis study investigated the cellular heterogeneity of HGSOC using scRNA-seq, focusing on tumor cell subtypes and their interactions within the tumor microenvironment. We confirmed the key role of the C2 IGF2+ tumor cell subtype in HGSOC, which was significantly associated with poor prognosis and high levels of chromosomal copy number variations. This subtype was located at the terminal differentiation of the tumor, displaying a higher degree of malignancy and close association with stage IIIC tissue types. The C2 subtype was also associated with various metabolic pathways, such as glycolysis and riboflavin metabolism, as well as programmed cell death processes. The study highlighted the complex interactions between the C2 subtype and fibroblasts through the MK signaling pathway, which may be closely related to tumor-associated fibroblasts and tumor progression. Elevated expression of PRRX1 was significantly connected to the C2 subtype and may impact disease progression by modulating gene transcription. A prognostic model based on the C2 subtype demonstrated its association with adverse prognosis outcomes, emphasizing the importance of immune infiltration and drug sensitivity analysis in clinical intervention strategies.ConclusionThis study integrates molecular oncology, immunotherapy, and drug sensitivity analysis to reveal the mechanisms driving HGSOC progression and treatment resistance. The C2 IGF2+ tumor subtype, linked to poor prognosis, offers a promising target for future therapies. Emphasizing immune infiltration and drug sensitivity, the research highlights personalized strategies to improve survival and quality of life for HGSOC patients.

A nanoscale natural drug delivery system for targeted drug delivery against ovarian cancer: action mechanism, application enlightenment and future potential

Ovarian cancer (OC) is one of the deadliest gynecological malignancies in the world and is the leading cause of cancer-related death in women. The complexity and difficult-to-treat nature of OC pose a huge challenge to the treatment of the disease, Therefore, it is critical to find green and sustainable drug treatment options. Natural drugs have wide sources, many targets, and high safety, and are currently recognized as ideal drugs for tumor treatment, has previously been found to have a good effect on controlling tumor progression and reducing the burden of metastasis. However, its clinical transformation is often hindered by structural stability, bioavailability, and bioactivity. Emerging technologies for the treatment of OC, such as photodynamic therapy, immunotherapy, targeted therapy, gene therapy, molecular therapy, and nanotherapy, are developing rapidly, particularly, nanotechnology can play a bridging role between different therapies, synergistically drive the complementary role of differentiated treatment schemes, and has a wide range of clinical application prospects. In this review, nanoscale natural drug delivery systems (NNDDS) for targeted drug delivery against OC were extensively explored. We reviewed the mechanism of action of natural drugs against OC, reviewed the morphological composition and delivery potential of drug nanocarriers based on the application of nanotechnology in the treatment of OC, and discussed the limitations of current NNDDS research. After elucidating these problems, it will provide a theoretical basis for future exploration of novel NNDDS for anti-OC therapy.

The emergence of DNAM-1 as the facilitator of NK cell-mediated killing in ovarian cancer

IntroductionOvarian cancer (OC) is the sixth most common malignancy in women and the poor 5-year survival emphasises the need for novel therapies. NK cells play an important role in the control of malignant disease but the nature of tumour-infiltrating and peripheral NK cells in OC remains unclear.MethodsUsing flow cytometric analysis, we studied the phenotype and function of NK cells in blood, primary tumour and metastatic tissue in 80 women with OC. The cell type contexture of metastatic OC tissue was explored utilising scRNAseq analysis, with a focus on portraying an immunogenic tumour microenvironment and determining the characteristics of a dysfunctional NK cell population.ResultsThe proportion of peripheral NK cells was markedly elevated with a highly activated profile and increased cytotoxicity. In contrast, NK cell numbers in primary tumour and metastasis were substantially reduced, with downregulation of activatory receptors together with elevated PD-1 expression. scRNA-Seq identified 5 NK cell subpopulations along with increased exhausted and immature NK cells within tumour tissue compared to normal tissue. These features were attenuated following chemotherapy where higher levels of activated and cytotoxic NK cells associated with improved disease-free survival. Correlation of NK cell phenotype with clinical outcomes revealed high levels of DNAM-1 expression on tissue-localised and peripheral NK cells to be associated with reduced survival. Expression of PVR, the DNAM-1 ligand, was significantly increased on tumours and DNAM-1 mediated NK cell lysis of primary tumour tissue was observed in vitro.DiscussionThese findings reveal profound modulation of the tumour tissue and systemic profile of NK cells which likely contributes to the high rates of local progression and metastasis seen with OC. Immunotherapeutic approaches that overcome local immune suppression and enhance DNAM-1-targeted lysis of OC offer the potential to improve disease control.

Integrated immunogenomic analyses of high-grade serous ovarian cancer reveal vulnerability to combination immunotherapy

Background The efficacy of immunotherapies in high-grade serous ovarian cancer (HGSOC) is limited, but clinical trials investigating the potential of combination immunotherapy including poly-ADP-ribose polymerase inhibitors (PARPis) are ongoing. Homologous recombination repair deficiency or BRCAness and the composition of the tumor microenvironment appear to play a critical role in determining the therapeutic response. Methods We conducted comprehensive immunogenomic analyses of HGSOC using data from several patient cohorts. Machine learning methods were used to develop a classification model for BRCAness from gene expression data. Integrated analysis of bulk and single-cell RNA sequencing data was used to delineate the tumor immune microenvironment and was validated by immunohistochemistry. The impact of PARPi and BRCA1 mutations on the activation of immune-related pathways was studied using ovarian cancer cell lines, RNA sequencing, and immunofluorescence analysis. Results We identified a 24-gene signature that predicts BRCAness. Comprehensive immunogenomic analyses across patient cohorts identified samples with BRCAness and high immune infiltration. Further characterization of these samples revealed increased infiltration of immunosuppressive cells, including tumor-associated macrophages expressing TREM2 , C1QA , and LILRB4 , as specified by single-cell RNA sequencing data and gene expression analysis of samples from patients receiving combination therapy with PARPi and anti-PD-1. Our findings show also that genomic instability and PARPi activated the cGAS-STING signaling pathway in vitro and the downstream innate immune response in a similar manner to HGSOC patients with BRCAness status. Finally, we have developed a web application ( https://ovrseq.icbi.at ) and an associated R package OvRSeq, which allow for comprehensive characterization of ovarian cancer patient samples and assessment of a vulnerability score that enables stratification of patients to predict response to the combination immunotherapy. Conclusions Genomic instability in HGSOC affects the tumor immune environment, and TAMs play a crucial role in modulating the immune response. Based on various datasets, we have developed a diagnostic application that uses RNA sequencing data not only to comprehensively characterize HGSOC but also to predict vulnerability and response to combination immunotherapy.

Immunoglobulin G Subclass-Specific Glycosylation Changes in Primary Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) was previously shown to be associated with glycosylation changes of total serum and total IgG proteins. However, as a majority of previous studies analyzed released glycan profiles, still little is known about IgG subclass-specific alterations in ovarian cancer. Hence, in this study, we investigated EOC-related glycosylation changes of the three most abundant IgG subclasses, namely, IgG

Characterization of immature ovarian teratomas through single-cell transcriptome

IntroductionImmature ovarian teratomas are a type of malignant germ cell tumor composed of complicated cell types and are characterized by pathological features of immature neuroectodermal tubules/rosettes. However, there is a lack of understanding of patient-derived immature ovarian teratomas (PDT) at the single cell level. Moreover, whether stem cell lines derived from immature teratomas (CDT) can be used as models for research on PDT remains to be elucidated.MethodsSingle-cell RNA sequencing (scRNA-seq) and subsequent bioinformatic analysis was performed on three patient-derived immature ovarian teratomas (PDT) samples to reveal the heterogeneity, evolution trajectory, and cell communication within the tumor microenvironment of PDT. Validations were conducted in additional seven samples through multiplex immunofluorescence.ResultA total of qualified 22,153 cells were obtained and divided into 28 clusters, which can match to the scRNA-seq annotation of CDT as well as human fetal Cell Atlas, but with higher heterogeneity and more prolific cell-cell crosstalk. Radial glia cells (tagged by SOX2) and immature neuron (tagged by DCX) exhibited mutually exclusive expression and differentiated along distinct evolutionary trajectory from cycling neural progenitors. Proportions of these neuroectodermal cell subtypes may play important roles in PDT through contributing to the internal heterogeneity of PDTs. Moreover, the immune cells in PDTs were infiltrated rather than teratoma-derived, with more abundant macrophage in immature neuron than those in radial glia cells, and the infiltrated macrophage subtypes (i.e., M1 and M2) were significantly correlated to clinical grade. Overall, suppressed evolution process and transcriptome regulation in neuroectodermal cells, reduced cell-cell crosstalk, higher M1/M2 proportion ratio, and enhanced T cell effects in tumor microenvironment are enriched in patients with favorable prognosis.DiscussionThis study provides a comprehensive profile of PDT at the single cell level, shedding light on the heterogeneity and evolution of neuroectodermal cells within PDTs and the role of immune cells within the tumor microenvironment. Also, our findings highlight the potential usage of CDTs as a model for research on PDT.

Decoding ascitic immunological niches with multi-modal machine learning reveals prognostic and chemoresistant determinants in ovarian cancer

Background Malignant ascites in high-grade serous ovarian cancer (HGSOC) represent a fluid extension of the tumor microenvironment, embedding immune programs that may inform prognosis and treatment response. We investigated whether ascitic T-cell phenotypes, integrated with clinical variables, improve prediction of overall survival (OS), progression-free survival (PFS), progression-free interval (PFI), and platinum-based drug chemotherapy resistance (P-DCR). Methods We retrospectively analyzed 87 patients with FIGO III/IV HGSOC with treatment-naïve ascites treated at Peking University Third Hospital (May 2019–Mar 2024; median follow-up, 33 months). Ascites (>1,000 mL) underwent standardized processing and multiparametric flow cytometry to quantify T-cell subsets. To prevent information leakage, we used repeated nested cross-validation with event-stratified folds: inner folds performed endpoint-specific screening with Benjamini–Hochberg FDR control, redundancy reduction, and multicollinearity checks; clinical covariates were added by incremental contribution testing. Cox proportional hazards, Random Survival Forests (RSFs), and DeepSurv modeled survival endpoints; a random-forest classifier modeled P-DCR. Performance was summarized on outer folds [C-index for survival; receiver operating characteristic–area under the curve (ROC-AUC) for P-DCR]. Model interpretability used Shapley Additive Explanations (SHAP). Results Across endpoints, combined clinical + ascites features outperformed single-source features, with RSF consistently best. Outer-fold testing C-indices for RSF with combined features were 0.72 (OS), 0.70 (PFS), and 0.74 (PFI). The P-DCR classifier achieved a mean AUC of 0.69 with combined features (accuracy, 0.66; sensitivity, 0.70; specificity, 0.62). Feature-count sensitivity analyses showed performance gains plateauing at modest k (≈5–7). Kaplan–Meier curves derived from combined-feature risk scores demonstrated clear stratification. SHAP analyses indicated protective effects of poly(ADP-ribose) polymerase (PARP) inhibitor maintenance across endpoints, while ascitic T-cell subsets, including PD-1 + CD57 + CD4 + and CCR7 - CD45RA + CD4 + populations, were repeatedly associated with higher risk; age contributed strongly to PFI. Conclusions Integrating ascitic immunophenotyping with clinical factors improves risk prediction in HGSOC, with RSF offering robust performance under rigorous, leakage-safe validation. Ascites-resident T-cell states provide complementary, reproducible prognostic signals for survival and platinum response, supporting their potential utility for patient stratification and hypothesis generation for immunomodulatory strategies.

Elevated Serum Human Epididymis Protein 4 Is Associated With Disease Activity and Systemic Involvements in Primary Sjögren’s Syndrome

BackgroundWe aimed to investigate the clinical utility of human epididymis protein 4, a tumor biomarker being widely utilized in clinical practice in the diagnosis of ovarian cancer, in primary Sjögren’s Syndrome (pSS).MethodsA total of 109 pSS patients and 113 healthy controls (HCs) were included in the study. HE4 were determined by Roche Cobas E601 electrochemical luminescence analyzer. Clinical and laboratory findings were reviewed, and the relationships between HE4 and clinical parameters were determined by Spearman’s correlation test. The European league against rheumatism Sjögren’s syndrome disease activity index (ESSDAI) was utilized to evaluate disease activity.FindingsThe levels of HE4 were significantly elevated in patients with pSS compared to HCs (103.65 pmol/L vs. 46.52 pmol/L, p<0.001). The levels of HE4 were positively correlated with ESSDAI scores (r=0.462, p<0.001). Significant positive correlations between the levels of HE4 with pulmonary involvements (r=0.442, p<0.001) and renal involvements (r=0.320, p=0.001) were observed. Receiver operating curve (ROC) analysis revealed an optimal cut-off value of 104.90 pmol/L and 128.05 pmol/L for distinguishing patients with pulmonary and renal involvements, with the areas under the ROC curve (AUCs) of 0.778 (95%CI 0.685-0.870, p<0.001) and 0.768 (95%CI 0.646-0.891, p=0.001), respectively. Among patients with pulmonary involvement, the levels of HE4 were positively correlated with the semiquantitative HRCT grade (r=0.417, p=0.016), and negatively correlated with the percentage of forced vital capacity (FVC) (r= -0.460, p=0.047) and diffusing capacity of the lung for carbon monoxide (DLco) (r= -0.623, p=0.004). For patients with renal involvement, HE4 was positively correlated with creatinine (r=0.588, p=0.021) and negatively correlated with estimated glomerular filtration rate (r= -0.599, p=0.030).ConclusionsOur findings demonstrated a novel role of HE4 in clinical stratification of pSS, suggesting that introducing HE4 to the current pSS test panel may provide additional diagnostic value, particularly in evaluating disease activity and pulmonary/renal involvements.

Current Advances in PD-1/PD-L1 Blockade in Recurrent Epithelial Ovarian Cancer

Immunotherapies have revolutionized the treatment of a variety of cancers. Epithelial ovarian cancer is the most lethal gynecologic malignancy, and the rate of advanced tumor progression or recurrence is as high as 80%. Current salvage strategies for patients with recurrent ovarian cancer are rarely curative. Recurrent ovarian cancer is a “cold tumor”, predominantly due to a lack of tumor antigens and an immunosuppressive tumor microenvironment. In trials testing programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) blockade as a monotherapy, the response rate was only 8.0-22.2%. In this review, we illustrate the status of cold tumors in ovarian cancer and summarize the existing clinical trials investigating PD-1/PD-L1 blockade in recurrent ovarian cancer. Increasing numbers of immunotherapy combination trials have been set up to improve the response rate of EOC. The current preclinical and clinical development of immunotherapy combination therapy to convert an immune cold tumor into a hot tumor and their underlying mechanisms are also reviewed. The combination of anti-PD-1/PD-L1 with other immunomodulatory drugs or therapies, such as chemotherapy, antiangiogenic therapies, poly (ADP-ribose) polymerase inhibitors, adoptive cell therapy, and oncolytic therapy, could be beneficial. Further efforts are merited to transfer these results to a broader clinical application.

Diagnostic and Therapeutic Approach in a Metastatic Vaginal Adenocarcinoma: A Case Report

BackgroundVaginal adenocarcinomas (VAC) are most often reported after intrauterine exposition to diethylstilbestrol (DES). Rarely, VACs are reported as a malignant transformation of vaginal adenosis or endometriosis, in the context of chromosomal abnormalities or malformations of the uterus or the vagina. VACs without DES exposition have a poor prognosis and a significantly worse outcome compared to vaginal squamous cell carcinomas or DES-associated VACs.ObjectiveHere, we report the case of a primarily metastatic VAC, treated successfully with different lines of chemo-, antiangiogenic, antibody, and immunotherapy.CaseThe 49-year-old patient presented in 5/2018 with a primarily pulmonary metastatic VAC. Significant tumor reduction was seen after six cycles of carboplatin AUC5/paclitaxel 175 mg/m²/bevacizumab 15 mg/kg q3w. Bevacizumab maintenance therapy and later cisplatin mono 50 mg/m² q2w led to local and distant tumor progression. To identify a potential targeted therapy, new tumor biopsies were obtained. Immunohistochemistry revealed ERBB2 expression, and paclitaxel 80 mg/m² weekly plus trastuzumab 4 mg/m² respectively 2 mg/m² q3w was administered. Due to local and pulmonal tumor progression after 6 months and persistent ERBB2 positivity, the therapy was adjusted to trastuzumab emtansine (T-DM1) 3.6 mg/kg q3w; however, the patient remained locally progressive after three cycles of T-DM1 and additionally showed a new bone metastasis. The new tumor biopsies revealed a combined positive score (CPS) of 2 regarding PD-L1, and pembrolizumab 200 mg q3w was initiated. The bone metastasis was radiated and treated with denosumab 120 mg q4w. Extreme tumor regression followed by stable disease was maintained for 9 months. Due to a slow locoregional progress only with new inguinal lymph node and pararectal lymph node metastases, a new tumor biopsy was taken. Molecular profiling showed an ARID1A mutation, a mutational burden of 5.1 mutations per megabase, and no genfusions. Based on these findings, therapy with PD-L1 antibodies, PD-1 antibodies, gemcitabine, or dasatinib was suggested. Therefore, administration of pembrolizumab was continued and local radiation therapy was performed. This led to a decrease in local tumor manifestations and a stable systemic disease.ConclusionOur case demonstrates the diagnostic and therapeutic approach in a patient with primary metastatic vaginal adenocarcinoma. By tumorgenetic profiling, different lines of systemic therapy, namely, antiangiogenic therapy, monoclonal antibody therapy, immunotherapy, and local radiation therapy, were identified and successfully administered.

The Immune Subtype Contributes to Distinct Overall Survival for Ovarian Cancer Patients With Platinum-Based Adjuvant Therapy

ObjectiveNowadays, platinum-based therapy has been widely used as the first-line therapy of ovarian cancer. However, the effect of the tumor microenvironment on platinum-based therapy remains unclear. In this study, we aim to investigate the relationship between immune microenvironment subtypes and the prognosis of platinum-based therapy in ovarian cancer.MethodsWe integrated 565 ovarian cancer samples from two datasets and obtained the immune subtypes (ISs) by consistent clustering of 1190 immune-related gene expressions. The proportional hazards regression model was used to assess the relationship between ISs and the prognosis of platinum-based adjuvant therapy including progression-free survival (PFS) and overall survival (OS). The prognostic contribution of ISs was validated in three additional cohorts. Non-parametric tests were used to assess genomic characteristics, the proportion of immune cells, and immune-related signature differences among ISs.ResultsWe identified and validated five ISs associated with different clinical outcomes of the platinum-based adjuvant therapy in ovarian cancer patients. These differences were only found in OS rather than PFS. An immune subtype had the worst OS. Those patients mainly derived from the mesenchymal subtype had the lowest tumor purity with a high leukocyte fraction as well as stromal fraction and had the highest TGF-β response signaling. By contrast, an immune subtype characterized by immunoreactive status with the highest CD8+T cell infiltration and elevated IFN-γ response signaling had the best prognosis. Other subtypes with more diverse immunologic features such as lowest macrophage regulation signaling showed intermediate prognoses. Notably, the contribution of ISs to OS was independent of the clinical response to platinum-based drugs.ConclusionOur analysis revealed the association between different immune characteristics and platinum-based adjuvant therapy, indicating the combination of ISs and chemotherapy could optimize the treatment strategy of OC patients.

Reactivity of NK Cells Against Ovarian Cancer Cells Is Maintained in the Presence of Calcium Phosphate Nanoparticles

Calcium phosphate nanoparticles (CaP-NPs) are biodegradable carriers that can be functionalized with biologically active molecules. As such, they are potential candidates for delivery of therapeutic molecules in cancer therapies. In this context, it is important to explore whether CaP-NPs impair the natural or therapy-induced immune cell activity against cancer cells. Therefore, in this study, we have investigated the effects of different CaP-NPs on the anti-tumor activity of natural killer (NK) cells using different ovarian cancer (OC) cell line models. We explored these interactions in coculture systems consisting of NK cells, OC cells, CaP-NPs, and therapeutic Cetuximab antibodies (anti-EGFR, ADCC-inducing antibody). Our experiments revealed that aggregated CaP-NPs can serve as artificial targets, which activate NK cell degranulation and impair ADCC directed against tumor targets. However, when CaP-NPs were properly dissolved by sonication, they did not cause substantial activation. CaP-NPs with SiO2-SH-shell induced some activation of NK cells that was not observed with polyethyleneimine-coated CaP-NPs. Addition of CaP-NPs to NK killing assays did not impair conjugation of NK with OC and subsequent tumor cytolytic NK degranulation. Therapeutic antibody coupled to functionalized CaP-NPs maintained substantial levels of antibody-dependent cellular cytotoxic activity. Our study provides a cell biological basis for the application of functionalized CaP-NPs in immunologic anti-cancer therapies.

PD-L1 and PD-L2 Expression in Cervical Cancer: Regulation and Biomarker Potential

PD-1/PD-L1 immune checkpoint inhibitors show potential for cervical cancer treatment. However, low response rates suggest that patient selection based on PD-L1 protein expression is not optimal. Here, we evaluated different PD-L1 detection methods and studied transcriptional regulation of PD-L1/PD-L2 expression by The Cancer Genome Atlas (TCGA) mRNAseq analysis. First, we determined the copy number of the PD-L1/PD-L2 locus by fluorescence in situ hybridization (FISH), PD-L1 mRNA expression by RNA in situ hybridization (RNAish), and PD-L1/PD-L2 protein expression by immunohistochemistry (IHC) on tissue microarrays containing a cohort of 60 patients. Additionally, distribution of PD-L1/PD-L2 was visualized based on flow cytometry analysis of single-cell suspensions (n = 10). PD-L1/PD-L2 locus amplification was rare (2%). PD-L1 mRNA expression in tumor cells was detected in 56% of cases, while 41% expressed PD-L1 protein. Discordant scores for PD-L1 protein expression on tumor cells between cores from one patient were observed in 27% of cases. Interestingly, with RNAish, PD-L1 heterogeneity was observed in only 11% of the cases. PD-L2 protein expression was found in 53%. PD-L1 mRNA and protein expression on tumor cells were strongly correlated (p < 0.001). PD-L1 and PD-L2 protein expression showed no correlation on tumor cells (p = 0.837), but a strong correlation on cells in stromal fields (p < 0.001). Co-expression of PD-L1 and PD-L2 on macrophage-like populations was also observed with flow cytometry analysis. Both PD-L1 and PD-L2 TCGA transcript levels strongly correlated in the TCGA data, and both PD-L1 and PD-L2 strongly correlated with interferon gamma (IFNG) expression/transcript levels (p < 0.0001). Importantly, patients with high PD-L1/PD-L2/IFNG transcript levels had a survival advantage over patients with high PD-L1/PD-L2 and low IFNG expression. Based on these findings, we conclude that PD-L1/PD-L2 expression in cervical cancer is mainly associated with interferon induction and not gene amplification, which makes FISH unsuitable as biomarker. The heterogeneous PD-L1 and PD-L2 expression patterns suggest IHC unreliable for patient selection. RNAish, in conjunction with interferon signaling evaluation, seems a promising technique for immune checkpoint detection. These results warrant further investigation into their prognostic and predictive potential.

Nocardia Rubra Cell Wall Skeleton Up-Regulates T Cell Subsets and Inhibits PD-1/PD-L1 Pathway to Promote Local Immune Status of Patients With High-Risk Human Papillomavirus Infection and Cervical Intraepithelial Neoplasia

The Nocardia rubra cell wall skeleton (Nr-CWS) for external use is an immune enhancer, which has been widely used in human cervix diseases such as cervical erosion, but the mechanism of Nr-CWS enhancing immunity is still unclear. The purpose of this study was to explore the effect and mechanism of Nr-CWS on the local immune status of cervical tissue in patients with high-risk human papillomavirus (HR-HPV) infection and cervical precancerous lesion, cervical intraepithelial neoplasia (CIN). The recruited patients with HR-HPV infection and CIN were treated with Nr-CWS. The specimens were taken from these patients before and after local application of Nr-CWS respectively. The normal control specimens were tested simultaneously. Serial section analysis of immunohistochemistry and co-expression analysis were performed to characterize populations of T cells and the expressions of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1). The levels of cytokines in local cervical tissue were also detected. Nr-CWS significantly increased T cells including CD4+, CD8+ T cells, and reduced the expression of PD-L1 in the patients’ local cervical tissues. Co-expression analyses showed that the proportions of PD-1+CD4+ cells in CD4+ T cells and PD-1+CD8+ cells in CD8+ T cells decreased after Nr-CWS application. Furthermore, the increase in the number of immune cells was accompanied by increased pro-inflammatory cytokines interleukin-12 (IL-12), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and decreased suppressive cytokine IL-10. The results indicate that Nr-CWS, as an immunotherapeutic agent for HR-HPV infection and CIN, plays an immune promoting role related to the upregulation of T cell subsets and the inhibition of PD-1/PD-L1 pathway.

A phase I trial of SON-1010, a tumor-targeted, interleukin-12-linked, albumin-binding cytokine, shows favorable pharmacokinetics, pharmacodynamics, and safety in healthy volunteers

BackgroundThe benefits of recombinant interleukin-12 (rIL-12) as a multifunctional cytokine and potential immunotherapy for cancer have been sought for decades based on its efficacy in multiple mouse models. Unexpected toxicity in the first phase 2 study required careful attention to revised dosing strategies. Despite some signs of efficacy since then, most rIL-12 clinical trials have encountered hurdles such as short terminal elimination half-life (T½), limited tumor microenvironment targeting, and substantial systemic toxicity. We developed a strategy to extend the rIL-12 T½ that depends on binding albumin in vivo to target tumor tissue, using single-chain rIL-12 linked to a fully human albumin binding (FHAB) domain (SON-1010). After initiating a dose-escalation trial in patients with cancer (SB101), a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 trial in healthy volunteers (SB102) was conducted.MethodsSB102 (NCT05408572) focused on safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. SON-1010 at 50-300 ng/kg or placebo administered subcutaneously on day 1 was studied at a ratio of 6:2, starting with two sentinels; participants were followed through day 29. Safety was reviewed after day 22, before enrolling the next cohort. A non-compartmental analysis of PK was performed and correlations with the PD results were explored, along with a comparison of the SON-1010 PK profile in SB101.ResultsParticipants receiving SON-1010 at 100 ng/kg or higher tolerated the injection but generally experienced more treatment-emergent adverse effects (TEAEs) than those receiving the lowest dose. All TEAEs were transient and no other dose relationship was noted. As expected with rIL-12, initial decreases in neutrophils and lymphocytes returned to baseline by days 9-11. PK analysis showed two-compartment elimination in SB102 with mean T½ of 104 h, compared with one-compartment elimination in SB101, which correlated with prolonged but controlled and dose-related increases in interferon-gamma (IFNγ). There was no evidence of cytokine release syndrome based on minimal participant symptoms and responses observed with other cytokines.ConclusionSON-1010, a novel presentation for rIL-12, was safe and well-tolerated in healthy volunteers up to 300 ng/kg. Its extended half-life leads to a prolonged but controlled IFNγ response, which may be important for tumor control in patients.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT05408572, identifier NCT05408572.

Recent advances in understanding the immune microenvironment in ovarian cancer

The occurrence of ovarian cancer (OC) is a major factor in women’s mortality rates. Despite progress in medical treatments, like new drugs targeting homologous recombination deficiency, survival rates for OC patients are still not ideal. The tumor microenvironment (TME) includes cancer cells, fibroblasts linked to cancer (CAFs), immune-inflammatory cells, and the substances these cells secrete, along with non-cellular components in the extracellular matrix (ECM). First, the TME mainly plays a role in inhibiting tumor growth and protecting normal cell survival. As tumors progress, the TME gradually becomes a place to promote tumor cell progression. Immune cells in the TME have attracted much attention as targets for immunotherapy. Immune checkpoint inhibitor (ICI) therapy has the potential to regulate the TME, suppressing factors that facilitate tumor advancement, reactivating immune cells, managing tumor growth, and extending the survival of patients with advanced cancer. This review presents an outline of current studies on the distinct cellular elements within the OC TME, detailing their main functions and possible signaling pathways. Additionally, we examine immunotherapy rechallenge in OC, with a specific emphasis on the biological reasons behind resistance to ICIs.

Vdelta1 T cells are more resistant than Vdelta2 T cells to the immunosuppressive properties of galectin-3

Ovarian carcinomas have the highest lethality amongst gynecological tumors. A problem after primary resection is the recurrence of epithelial ovarian carcinomas which is often associated with chemotherapy resistance. To improve the clinical outcome, it is of high interest to consider alternative therapy strategies. Due to their pronounced plasticity, γδ T cells are attractive for T-cell-based immunotherapy. However, tumors might escape by the release of lectin galectin-3, which impairs γδ T-cell function. Hence, we tested the effect of galectin-3 on the different γδ T-cell subsets. After coculture between ovarian tumor cells and Vδ1 or Vδ2 T cells enhanced levels of galectin-3 were released. This protein did not affect the cytotoxicity of both γδ T-cell subsets, but differentially influenced the proliferation of the two γδ T-cell subsets. While increased galectin-3 levels and recombinant galectin-3 inhibited the proliferation of Vδ2 T cells, Vδ1 T cells were unaffected. In contrast to Vδ1 T cells, the Vδ2 T cells strongly upregulated the galectin-3 binding partner α3β1-integrin after their activation correlating with the immunosuppressive properties of galectin-3. In addition, galectin-3 reduced the effector memory compartment of zoledronate-activated Vδ2 T cells. Therefore, our data suggest that an activation of Vδ1 T-cell proliferation as part of a T-cell-based immunotherapy can be of advantage.

Improved overall survival in patients with high-grade serous ovarian cancer is associated with CD16a+ immunologic neighborhoods containing NK cells, T cells and macrophages

BackgroundFor patients with high grade serous carcinoma of the ovary (HGSC), survival rates have remained static for the last half century. Despite the presence of tumor mutations and infiltration of immune cells, existing immunotherapies have achieved little success against HGSC. These observations highlight a gap in the understanding of how the immune system functions and interacts within HGSC tumors.MethodsWe analyzed duplicate core samples from 939 patients with HGSC to understand patterns of immune cell infiltration, localization, and associations with clinical features. We used high-parameter immunohistochemical/Opal multiplex, digital pathology, computational biology, and multivariate analysis to identify immune cell subsets and their associations with HGSC tumors.ResultsWe defined six patterns of cellular infiltration by spatially restricted unsupervised clustering of cell subsets. Each pattern was represented to some extent in most patient samples, but their specific distributions differed. Overall (OS) and progression-free survival (PFS) corresponded with higher infiltration of CD16a+ cells, and their co-localization with macrophages, T cells, NK cells, in one of six cellular neighborhoods that we defined with our spatial assessment.ConclusionsImmune cell neighborhoods containing CD16a+ cells are associated with improved OS and PFS for patients with HGSC. Patterns of immunologic neighborhoods differentiate patient outcomes, and could inform future, more precise approaches to treatment.

Specific changes in amino acid profiles in monocytes of patients with breast, lung, colorectal and ovarian cancers

IntroductionImmunometabolism is essential factor of tumor progression, and tumor-associated macrophages are characterized by substantial changes in their metabolic status. In this study for the first time, we applied targeted amino acid LC-MS/MS analysis to compare amino acid metabolism of circulating monocytes isolated from patients with breast, ovarian, lung, and colorectal cancer.MethodsMonocyte metabolomics was analyzed by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/ MS) analysis of amino acid extracts. The targeted analysis of 26 amino acids was conducted by LCMS/MS on an Agilent 6460 triple quadrupole mass spectrometer equipped with an electrospray ionization source and an Agilent 1260 II liquid chromatograph.ResultsComparison of monocytes of cancer patients with monocytes of healthy control individuals demonstrated that in breast cancer most pronounced changes were identified for tryptophan (AUC = 0.76); for ovarian cancer, aminobutyric acid was significantly elevated (AUC= 1.00); for lung cancer significant changes we indented for citrulline (AUC = 0.70). In order to identify key amino acids that are characteristic for monocytes in specific cancer types, we compared each individual cancer with other 3 types of cancer. We found, that aspartic acid and citrulline are specific for monocytes of patients with colorectal cancer (p<0.001, FC = 1.40 and p=0.003, FC = 1.42 respectively). Citrulline, sarcosine and glutamic acid are ovarian cancer-specific amino acids (p = 0.003, FC = 0.78, p = 0.003, FC = 0.62, p = 0.02, FC = 0.78 respectively). Glutamine, methionine and phenylalanine (p = 0.048, FC = 1.39. p = 0.03, FC = 1.27 and p = 0.02, FC = 1.41) are lung cancer-specific amino acids. Ornithine in monocytes demonstrated strong positive correlation (r = 0.63) with lymph node metastasis incidence in breast cancer patients. Methyl histidine and cysteine in monocytes had strong negative correlation with lymph node metastasis in ovarian cancer patients (r = -0.95 and r = -0.95 respectively). Arginine, citrulline and ornithine have strong negative correlation with tumor size (r = -0.78, citrulline) and lymph node metastasis (r = -0.63 for arginine and r = -0.66 for ornithine).DiscussionThese alterations in monocyte amino acid metabolism can reflect the reaction of systemic innate immunity on the growing tumor. Our data indicate that this metabolic programming is cancer specific and can be inhibiting cancer progression. Cancer-specific differences in citrulline, as molecular link between metabolic pathways and epigenetic programing, provide new option for the development and validation of anti-cancer therapies using inhibitors of enzymes catalyzing citrullination.

Epithelial ovarian cancer is infiltrated by activated effector T cells co-expressing CD39, PD-1, TIM-3, CD137 and interacting with cancer cells and myeloid cells

IntroductionDespite predicted efficacy, immunotherapy in epithelial ovarian cancer (EOC) has limited clinical benefit and the prognosis of patients remains poor. There is thus a strong need for better identifying local immune dynamics and immune-suppressive pathways limiting T-cell mediated anti-tumor immunity.MethodsIn this observational study we analyzed by immunohistochemistry, gene expression profiling and flow cytometry the antigenic landscape and immune composition of 48 EOC specimens, with a focus on tumor-infiltrating lymphocytes (TILs).ResultsActivated T cells showing features of partial exhaustion with a CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ surface profile were exclusively present in EOC specimens but not in corresponding peripheral blood or ascitic fluid, indicating that the tumor microenvironment might sustain this peculiar phenotype. Interestingly, while neoplastic cells expressed several tumor-associated antigens possibly able to stimulate tumor-specific TILs, macrophages provided both co-stimulatory and inhibitory signals and were more abundant in TILs-enriched specimens harboring the CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ signature.ConclusionThese data demonstrate that EOC is enriched in CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ T lymphocytes, a phenotype possibly modulated by antigen recognition on neoplastic cells and by a combination of inhibitory and co-stimulatory signals largely provided by infiltrating myeloid cells. Furthermore, we have identified immunosuppressive pathways potentially hampering local immunity which might be targeted by immunotherapeutic approaches.

Dual PD-1 and CTLA-4 targeting in endometrial carcinoma: integrating efficacy, toxicity, and biomarkers into clinical practice

The management of advanced endometrial cancer (EC) has been transformed by immunotherapy, raising a pivotal clinical challenge: selecting patients with mismatch repair–deficient (dMMR) disease for intensive dual PD-1/CTLA-4 blockade versus standard PD-1 monotherapy. We conducted a narrative review of phase II/III clinical trials and key translational studies published up to 2023 to critically appraise current evidence. In dMMR EC, the conventional ipilimumab-nivolumab combination yields higher objective response rates (ORR ≈ 63%) than PD-1 monotherapy (ORR ≈ 48%) but is associated with a substantially increased incidence of grade ≥ 3 immune-related adverse events (≈ 23% vs. ≈ 12%). The development of bispecific antibodies like cadonilimab, which demonstrates robust efficacy with a lower incidence of high-grade toxicity (grade ≥ 3 treatment-related adverse events: 8.3%), presents a promising strategy to improve the therapeutic index. For clinicians, the current decision-making process must be highly individualized, weighing factors such as tumor burden, pace of disease, and patient tolerance for toxicity in the absence of validated biomarkers to guide treatment intensity beyond dMMR status. We also addressed the critical importance of accurate MMR/MSI testing and the clinical implications of a well-documented methodological discordance rate. In contrast, for patients with mismatch repair–proficient (pMMR) tumors, the evidence firmly supports alternative regimens, such as lenvatinib plus pembrolizumab, over dual PD-1/CTLA-4 blockade. Navigating the evolving landscape of immunotherapy in EC requires a nuanced, patient-centric approach. The integration of novel bispecific antibodies may soon simplify the balance between efficacy and toxicity, but until then, treatment selection remains a deliberate process, underscoring the gynecologic oncologist’s pivotal role in personalizing care.

The dysregulation of the immune microenvironment during endometrial intraepithelial neoplasia serves as a marker of endometrial carcinogenesis

The development of endometrial cancer is a gradual malignant transformation process driven by multiple factors, and the immune microenvironment is closely related to clinical outcomes and immunotherapy responses. Under physiological conditions, the immune microenvironment of the normal endometrium undergoes periodic reshaping under the regulation of estrogen and progesterone, maintaining the balance between immune defense and reproductive capacity. However, continuous exposure to risk factors, such as non-antagonistic estrogen, may trigger endometrial intraepithelial neoplasia. During this period, the immune microenvironment becomes dysregulated, supporting malignant progression. For example, estrogen-stimulated interactions between endothelial cells and macrophages, elevated neutrophil/lymphocyte ratios, and the accumulation of regulatory T cells all combine to cause dysregulation of immune microenvironment. The abnormal immune microenvironment that occurs in the precancerous lesion stage interacts with systemic and genetic carcinogenic factors, ultimately shaping the unique immune microenvironment of each molecular subtype of endometrial cancer. POLE-mutated and MSI-H subtype endometrial cancer are immune-infiltrated tumors, whereas the copy-number high subtype is immune-suppressive tumor and the copy-number low subtype is immune-desert tumor. However, still little is known about the immune dysregulation that occurs during the precancerous stage and its impact on subsequent malignant progression. This review systematically describes the changes in the immune microenvironment during the process from normal endometrium to endometrial cancer, emphasizing that endometrial intraepithelial neoplasia is a key stage of immune imbalance, thus paving the way for early immune intervention and precise immunotherapy.

Soluble immune checkpoints in endometrial cancer – a discovery study

Background Soluble immune checkpoints (sICs) are circulating forms of membrane-bound immune molecules, the latter being targets of immune checkpoint inhibitors, widely used in cancer treatment. Altered sIC levels have been reported in several malignancies and sICs are posited as promising diagnostic, prognostic and predictive biomarkers measurable in peripheral blood. However, data on their levels in endometrial cancer (EC) patients are scarce. This study aimed to evaluate plasma concentrations of multiple sICs in EC patients and assess their potential diagnostic, prognostic, and predictive value. Methods In this prospective case–control study, plasma levels of 16 soluble immune checkpoints were measured in 50 patients with histologically confirmed EC prior to surgical staging and in 26 age- and BMI-matched controls undergoing benign gynecologic surgery. Fluorescence-based multiplex immunoassay (MagPix, Luminex) was used to quantify analyte concentrations. FIGO 2023 stage classification and risk grouping according to ESGO 2020 guidelines was performed based on clinicopathologic data and molecular characteristics (MMR and p53 status). Statistical analyses were performed using non-parametric tests and robust logistic regression. Results EC and control groups did not differ in demographic, clinical, or lifestyle parameters. sIC levels were measurable in majority of patients. No significant differences in sIC levels were observed between EC patients and controls. Within the EC cohort, patients with MMR-deficient tumors exhibited significantly elevated levels of sPD-1, sPD-L1, sLAG-3, sICOS, sGITR, and sCD86 compared with MMR-proficient cases. Higher plasma concentrations of sTIM-3, sCD27, sHVEM, and sCD40 were associated with the presence of lymphovascular space invasion (LVSI). Levels of sCD27 and sCD40 were significantly higher in advanced or metastatic disease (stage IIIA or higher). Conclusions Although soluble immune checkpoint levels did not differentiate EC patients from controls, several sICs correlated with key prognostic and predictive features, including LVSI, advanced stage, and MMR deficiency. These findings suggest that circulating immune checkpoint proteins may serve as non-invasive biomarkers for risk assessment and immunotherapy response prediction in endometrial cancer. Further validation in larger, independent cohorts is warranted.

Subtyping of Human Papillomavirus-Positive Cervical Cancers Based on the Expression Profiles of 50 Genes

BackgroundHuman papillomavirus-positive (HPV+) cervical cancers are highly heterogeneous in molecular and clinical features. However, the molecular classification of HPV+ cervical cancers remains insufficiently unexplored.MethodsBased on the expression profiles of 50 genes having the largest expression variations across the HPV+ cervical cancers in the TCGA-CESC dataset, we hierarchically clustered HPV+ cervical cancers to identify new subtypes. We further characterized molecular, phenotypic, and clinical features of these subtypes.ResultsWe identified two subtypes of HPV+ cervical cancers, namely HPV+G1 and HPV+G2. We demonstrated that this classification method was reproducible in two validation sets. Compared to HPV+G2, HPV+G1 displayed significantly higher immune infiltration level and stromal content, lower tumor purity, lower stemness scores and intratumor heterogeneity (ITH) scores, higher level of genomic instability, lower DNA methylation level, as well as better disease-free survival prognosis. The multivariate survival analysis suggests that the disease-free survival difference between both subtypes is independent of confounding variables, such as immune signature, stemness, and ITH. Pathway and gene ontology analysis confirmed the more active tumor immune microenvironment in HPV+G1 versus HPV+G2.ConclusionsHPV+ cervical cancers can be classified into two subtypes based on the expression profiles of the 50 genes with the largest expression variations across the HPV+ cervical cancers. Both subtypes have significantly different molecular, phenotypic, and clinical features. This new subtyping method captures the comprehensive heterogeneity in molecular and clinical characteristics of HPV+ cervical cancers and provides potential clinical implications for the diagnosis and treatment of this disease.

SLC40A1-mediated positive feedback loop with M1 macrophages suppresses epithelial ovarian cancer progression

Introduction Ovarian cancer (OC), particularly epithelial ovarian cancer (EOC), represents one of the most lethal and aggressive gynecological malignancies. Despite advances in surgery, chemotherapy, and immunotherapy, patient survival remains poor. Identifying novel molecular targets is crucial for improving early diagnosis and developing more effective therapies. Methods We examined the expression and immunoregulatory function of SLC40A1 in EOC using both experiments on cells and mouse orthotopic tumor models. Through integrated in vitro and in vivo studies, we systematically assessed the role of SLC40A1 in promoting M1 macrophage polarization and its relationship with tumor suppression, demonstrating that SLC40A1 enhances the response to immunotherapy. Results SLC40A1 was found to be more highly expressed in normal ovarian tissues compared with EOC tissues, and its high expression was associated with a favorable prognosis. In vitro , SLC40A1 did not significantly affect tumor cell proliferation, apoptosis, or migration and invasion. However, in vivo experiments using mice with differing immune status demonstrated that SLC40A1 modulates the tumor immune microenvironment. Subsequent bioinformatics analyses suggested that SLC40A1 may regulate M1 macrophage polarization. Mechanistically, in vitro experiments confirmed that SLC40A1 regulates CXCL11 secretion, which activates the JAK2–STAT1 signaling pathway, promoting macrophage TNF-α production, which in turn upregulates SLC40A1 expression. Finally, we demonstrated that SLC40A1 enhances the response to immunotherapy. Discussion These findings identify SLC40A1 as a key regulator of the antitumor immune response in EOC. High SLC40A1 expression is associated with enhanced macrophage-mediated tumor suppression and improved response to immunotherapy, highlighting its potential as both a prognostic biomarker and a therapeutic target.

Identification of Interleukin-9 Producing Immune Cells in Endometrial Carcinoma and Establishment of a Prognostic Nomogram

BackgroundInterleukin-9 (IL9) plays a critical role in immunity and the pathogenesis of endometrial cancer (EC), especially endometrioid EC (EEC). This study aimed to identify the IL9+ immune cell subsets and their pleiotropic functions and establish an optimized prognostic nomogram towards the promotion of personalized treatment of EEC.Methods1,417 EC patients were involved in the present study. 143 patients from the tertiary gynecology centers in Shanghai between 2013 and 2019 were recruited, and the study protocol was approved by the Institutional Review Board (IRB) of Shanghai First Maternity and Infant Hospital. The genomic data of the other 1,274 patients were extracted from the TCGA and the MSKCC datasets, respectively. Immune and stromal scores were calculated using the ESTIMATE R tool, and the tumor infiltration of immune cells was analyzed using the TIMER platform. Metascape and GEPIA datasets were used for bioinformatic analysis. P < 0.05 was considered statistically significant. All statistical analyses were performed with GraphPad Prism and R studio.Results552 genes that were correlated with leukocyte infiltration, lymphocyte activation, and regulation of innate immune response were up-regulated in the high immune score group. More IL9+ cell infiltration was detected in the highly and moderately differentiated EC (p = 0.04). High IL9+ lymphocyte infiltration was related to a better overall survival (p = 0.0027). IL9 positive cell clusters included ILC2s, Vδ2 γδT cells, mast cells, macrophages, and Th9 cells. Parameters such as FIGO stage, IL9 score, Vδ2 + γδT cell infiltration, classification of differentiation, and diabetes mellitus were assigned a weighted number of points in the nomogram for a specific predicted 3-, 5- and 10-year overall survival (OS). IL9–IL9R axis played a vital role in EEC, IL9R positive cell subgroups were also identified, and the related function was analyzed in the present study. Additionally, PR (Progesterone Receptor, or PGR) expression was relevant to a higher density of IL9+ lymphocyte infiltration. However, PGRMC1 (Progesterone Receptor Membrane Component 1) was negatively relevant to IL9R (p = 4.26e-8).ConclusionWe observed a significant infiltration of IL9+ cells and the overrepresentation of IL-9R in tissue specimens of patients in EC cases. The nomogram incorporating the IL9 could accurately predict individualized survival probability in EEC. Additionally, this study not only established a prognostic nomogram but also assist in the firmer understanding of the relevance of the IL9-IL9R axis and IL9-producing cells in EC immunity.