Bin Yang

Hypoxia-driven remodeling of SELENOP+ macrophages shapes T cell dynamics and promotes ovarian cancer metastasis

Abstract High-grade serous ovarian cancer (HGSOC) is characterized by extensive transcoelomic dissemination and the accumulation of ascites. However, how site-specific tumor microenvironment (TME) drives progression remains unknown. Here we show the co-occurrence and spatial co-localization of SELENOP + macrophages and precursor exhausted CD8 + T cells and demonstrate that SELENOP + macrophages activate T cells via selenoprotein P in vitro and in vivo. We further identify a dynamic transition in the SELENOP + / SPP1 + macrophage populations as tumor metastasis, driven by increased hypoxia malignant epithelial cells through VEGFA-EPHB2 signaling. We also reveal that anti-VEGFA intervention controls ovarian tumor growth by increasing SELENOP + macrophages and cytotoxicity of CD8 + T cells in vivo. Taken together, these findings spotlight the role of tumor-induced TME remodeling in subverting immune-mediated tumor control and thus facilitating HGSOC metastasis in females. Collectively, our results provide a foundation for the development of targeted therapeutic interventions aimed at impeding HGSOC metastatic trajectory.

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation

AbstractHyperthermic intraperitoneal chemotherapy’s role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.

Heterogeneous cellular responses to hyperthermia support combined intraperitoneal hyperthermic immunotherapy for ovarian cancer mouse models

The benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer remains controversial, hindering the development of rational combination therapies based on hyperthermia (HT). This study reports the preliminary results of the neoadjuvant HIPEC (NHIPEC) trial (ChiCTR2000038173), demonstrating enhanced tumor response in high-grade serous ovarian cancer with NHIPEC. Through single-cell RNA sequencing analysis, we identified both homogeneous and heterogeneous cellular responses to HT within the tumor and microenvironment. Epithelial-mesenchymal transition–activated tumor cells and matrix metallopeptidase 11 (MMP-11) + cancer-associated fibroblasts (CAFs) exhibited greater reductions and higher sensitivity to HT. CUT&Tag and RNA sequencing integration unveiled the differential binding programs and transcriptional regulatory mechanisms of HSF1 under normothermia (NT) and HT in tumor cells and CAFs. Furthermore, HT ameliorated the immunosuppressive tumor microenvironment, and in vivo mouse models confirmed the combined antitumor effects of HT and programmed cell death ligand 1 blockade. These findings provide an innovative strategy for rational combination therapy with HT in ovarian cancer.

GLUT1 Expression Patterns in Verruciform Acanthotic Vulvar Squamous Intraepithelial Neoplasia, HPV–Independent p53 Wild-Type Squamous Cell Carcinoma and Benign Vulvar Lesions

Verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN) is a rare type of human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (SCC) precursor lacking aberrant p53 expression. Our recent study demonstrated GLUT1 overexpression in vulvar SCC and identified 2 distinct patterns in HPV-associated high-grade squamous intraepithelial lesions and HPV-independent differentiated vulvar intraepithelial neoplasia. Herein, we expand on our study by assessing GLUT1 expression in 24 cases of vaVIN and 8 cases of associated invasive SCC, compared with 48 cases of benign vulvar squamous lesions, including 40 cases of non-HPV benign vulvar lesions and 8 cases of condyloma associated with low-risk HPV infection. GLUT1 immunohistochemistry (IHC) demonstrated consistent diffuse GLUT1 immunostaining in all vaVIN cases. The GLUT1 immunostaining pattern in vaVIN is characterized by strong membranous staining in the basal layer with suprabasal extension to the full thickness of intermediate layers. In vulvar SCC associated with vaVIN, GLUT1 expression was prominent at the periphery of tumor nests without expression in the central portion. GLUT1 IHC revealed weak peri-papillae or intensified peri-papillae patterns in non-neoplastic vulvar lesions and HPV-related patterns in condyloma. The GLUT1 immunostaining patterns in vaVIN and associated SCC are different from benign mimickers, but similar to those of differentiated vulvar intraepithelial neoplasia and associated SCC, despite distinct molecular alterations and pathways. The latter suggests that upregulation of GLUT1 is likely a common metabolic pathway shared by 2 types of HPV-independent VINs, regardless of p53 status. GLUT1 IHC is highly sensitive in detecting vaVIN. However, the specificity rests on recognizing GLUT1-staining patterns in benign mimickers of vaVIN. Along with HPV chromogenic in situ hybridization and other well-characterized biomarkers, GLUT1 immunochemistry can be a helpful adjunct in assisting the diagnosis of vaVIN.

Distinct Patterns of GLUT1 Expression in Human Papillomavirus Associated and Human Papillomavirus Independent Vulvar Intraepithelial Neoplasia and Squamous Cell Carcinoma

The expression of GLUT1 in vulvar squamous cell carcinoma (SCC) and its precursors remains largely unknown. We systematically investigated GLUT1 expression in human papillomavirus (HPV)-associated and HPV-independent vulvar intraepithelial neoplasia (VIN) and SCC. Our study had a total of 240 cases, including 40 cases of non-neoplastic vulva, 45 HPV-associated high-grade squamous intraepithelial lesions (HSILs), 65 HPV-independent VINs, and 90 invasive SCCs. Immunohistochemical analysis revealed that GLUT1 was expressed noncontinuously at the basal layer near stromal papillae in most non-neoplastic vulvar squamous epithelium. Overexpression of GLUT1 was observed in 82.2% and 88.9% of HPV-associated HSIL and SCC, respectively, compared with 96.9% and 100% of HPV-independent VIN and SCC. Two distinct patterns of the GLUT1 expression were observed in HPV-associated and HPV-independent VIN and SCC. In HPV-associated HSIL, overexpression of GLUT1 was mainly noted in the upper intermediate layers, accompanied by negative or weak immunostaining in the basal and parabasal layers. Similar patterns were also found in HPV-associated SCC, characterized by increased GLUT1 staining intensity in the centers of tumor sheets or nests with spared basal peripheral layers. Conversely, intense membranous GLUT1 staining was mainly observed in the basal and suprabasal layers in HPV-independent VIN, regardless of p53 status. Similar intense basal and parabasal GLUT1 staining patterns and no or weak staining intensity in central areas were seen in HPV-independent SCCs. In conclusion, overexpression of GLUT1 was found in most vulvar SCCs and their precursors. We identified 2 distinct GLUT1 patterns between HPV-associated and HPV-independent VINs and SCCs. Given its high sensitivity, immunohistochemistry for GLUT1 can be a valuable tool for facilitating accurate diagnosis of VIN, especially the HPV-independent type.

Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance

Cervical squamous cell carcinoma (CSCC) exhibits a limited response to immune-checkpoint blockade. Here we conducted a multiomic analysis encompassing single-cell RNA sequencing, spatial transcriptomics and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially resolved map of intratumoral expression heterogeneity in CSCC. Three tumor states (epithelial-cytokeratin, epithelial-immune (Epi-Imm) and epithelial senescence), recapitulating different stages of squamous differentiation, showed distinct tumor immune microenvironments. Bidirectional interactions between epithelial-cytokeratin malignant cells and immunosuppressive cancer-associated fibroblasts form an immune exclusionary microenvironment through transforming growth factor β pathway signaling mediated by FABP5. In Epi-Imm tumors, malignant cells interact with natural killer and T cells through interferon signaling. Preliminary analysis of samples from a cervical cancer clinical trial ( NCT04516616 ) demonstrated neoadjuvant chemotherapy induces a state transition to Epi-Imm, which correlates with pathological complete remission following treatment with immune-checkpoint blockade. These findings deepen the understanding of cellular state diversity in CSCC.

Risk of ovarian cancer in women with pelvic inflammatory disease and homologous recombination repair gene mutations under 55: a population-based cohort study

To address the relation among pelvic inflammatory disease (PID), genetic vulnerability and ovarian cancer (OC) risk, we assessed the association between PID and OC risk, alongside the interplay with germline homologous recombination repair (gHR) mutation, utilizing the UK Biobank. We conducted a prospective cohort study in the UK Biobank by tracking OC incidences between individuals with and without a PID history. Identification of gHR mutations ( In the large prospective cohort study, the adjusted HR for OC in patients with PID was 1.45 (95% confidence interval [CI]=0.90, 2.32) compared with those with non-PID. Intriguingly, age-stratified analysis unveiled a positive association between PID history and OC risk in those aged under 55 years (HR=1.92; 95% CI=1.02, 3.63). Moreover, individuals aged younger than 55 years harboring both a history of PID and gHR mutations exhibited the highest risk of OC (HR=7.40; 95% CI=1.03, 53.10). An association between PID and OC risk emerged, notably in the subgroup aged younger than 55 years old. Individuals with both a PID history and gHR mutations exhibited the highest risk of OC. These findings imply PID as a potential precursor for OC, underscoring the importance of early intervention, particularly in the younger population with gHR mutations.

Retained PAX2 expression associated with DNA mismatch repair deficiency in endometrial endometrioid adenocarcinoma

AimsLoss of expression of tumour suppressor PAX2 and MMR deficiency (dMMR) has been frequently seen in endometrial endometrioid adenocarcinoma (EEC). However, the relationship between PAX2 expression and MMR status is unknown.Methods and ResultsWe studied the PAX2 expression and examined its association with MMR status at the protein and genetic levels in 180 cases of EEC. Overall, total loss of PAX2 expression was found in about 70%, while retained PAX2 expression was seen in 30% of EEC. Among 125 cases with loss of PAX2, 68.8% were found in EECs with pMMR, while 31.2% were seen in those with dMMR. Among 55 cases of EECs with retained PAX2 expression, 92.7% were EECs with dMMR and 7.3% were those with pMMR (P < 0.001). While dMMR cases with MLH1 hypermethylation show almost equal retained or loss of PAX2 expression (52% versus 48%), dMMR with genetic alterations had significantly more retained PAX2 expression than loss of PAX2 (92.3% versus 7.7%), regardless of somatic or germline mutations. Loss of PAX2 was observed in 97.3% of dMMR with MLH1 hypermethylation compared to 2.7% of dMMR with genetic alterations (P < 0.001). Aggressive features such as higher tumour grades (FIGO 2–3) and advanced clinical stage (T2–T4) were significantly more frequently seen in dMMR with retained PAX2 expression, compared those to pMMR with loss of PAX2 expression.ConclusionOur study demonstrates a close correlation between retained PAX2 expression and dMMR in EEC. The molecular mechanism and clinical significance linking these two pathways in EEC remains to be unravelled.

Pd-1 Antibody Combined Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer

Cervical cancer is one of the major health problems for chinese women. Besides surgery and radiotherapy, neoadjuvant chemotherapy has been proved to be an effective program by many studies. However, not all patients respond well to neoadjuvant chemotherapy. This is an open-label, single-arm, multi-center clinical trial to evaluate whether PD-1 in combination with neoadjuvant chemotherapy will achieve better objective response rate.