Qin Liu

Molecular and Immune Correlates of Response to First-Line De-escalated Chemotherapy plus Penpulimab and Anlotinib in Advanced Cervical Cancer

Abstract The standard of care for advanced cervical cancer includes chemotherapy, antiangiogenic, and/or immune checkpoint blockade regimens. Although effective, it leads to pleiotropic side effects. Deescalation chemotherapy together with immunotargeted therapies has been proven effective and less toxic in other cancers. In this study, we conducted a multicenter, single-arm, phase II study of first-line deescalated platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab in patients with PD-L1–positive, persistent, recurrent, or metastatic cervical cancer. Of 32 efficacy-evaluable patients, 30 (93.8%, 95% confidence interval, 79.2%–99.2%) had an investigator-confirmed objective response. Single-nucleus RNA sequencing implied enhanced chemotaxis and proliferative activity of tumor-infiltrating T cells, and activated germinal center B cells portended optimal treatment response. Patients with a high tertiary lymphoid structure-to-tumor area ratio exhibited better survival. Our findings lay the groundwork for the feasibility of first-line de-escalated chemotherapy plus anlotinib and penpulimab in patients with metastatic, persistent, or recurrent cervical cancer. Significance: We recruited 34 patients with advanced cervical cancer receiving two cycles of platinum-based chemotherapy plus anlotinib and penpulimab, followed by maintenance therapy solely with anlotinib and penpulimab, and showed safety and efficacy of this deescalation regimen. This work highlights the potential for personalized treatment strategies and feasibility of reduced-toxicity regimens.

LncRNA FAM225B Regulates PDIA4-Mediated Ovarian Cancer Cell Invasion and Migration via Modulating Transcription Factor DDX17

Objective. This study aimed to explore the roles and mechanisms of lncRNA FAM225B and PDIA4 in ovarian cancer. Methods. RT-qPCR and Western blot assays were performed to detect the expression levels of the lncRNAs FAM225B, DDX17, and PDIA4 in the serum of patients with ovarian cancer and cell lines. Cells were transfected with lncRNA FAM225B- and PDIA4-related vectors to determine the malignant phenotypes using functional experiments. The mutual binding of lncRNA FAM225B and DDX17 was verified using RNA pull-down and RIP assays. Results. The expression of lncRNAs FAM225B and PDIA4 was decreased in the serum of patients with ovarian cancer and cell lines. Restoration of lncRNA FAM225B or PDIA4 reduced cell proliferation, migration, and invasion abilities and elevated the apoptosis rate, whereas suppression of lncRNA FAM225B or PDIA4 exhibited an inverse trend. RNA pull-down and RIP assays revealed a direct interaction between lncRNA FAM225B and DDX17. ChIP assay revealed a relationship between DDX17 and the PDIA4 promoter. LncRNA FAM225B and DDX17 positively regulate PDIA4 expression. Downregulation of PDIA4 expression counteracts the suppressive effect of lncRNA FAM225B overexpression in ovarian cancer cells. Conclusion. This research study supports the fact that lncRNA FAM225B in ovarian cancer can upregulate PDIA4 by directly binding to DDX17, inhibiting the activities of ovarian cancer cells.

Lymphocyte and macrophage infiltration in omental metastases indicates poor prognosis in advance stage epithelial ovarian cancer

Objective To investigate the prognostic value of immune cells within omental metastases originating from advanced epithelial ovarian cancer (EOC). Methods We performed immunohistochemical analysis to determine the levels of CD4+/CD8+ tumor-infiltrating lymphocytes (TILs) and CD68+ tumor-associated microphages (TAMs) in omental specimens from 100 patients with advanced EOC. Significant prognostic factors, including immune cells and clinical parameters, were assessed by Kaplan–Meier survival analysis and Cox models. Results Cox regression analysis showed that elevated levels of CD68+ TAMs and intra-islet CD4+ TILs in omental metastases were the main risk factors associated with worse survival outcomes for advanced EOC. Moreover, the survival analysis of relationships between omental immune cells and favorable clinical predictors revealed additional prognostic stratification information. Conclusion Omental immune cells (TAMs and TILs) provide alternative prognostic factors in advanced EOC. In contrast to markers of the EOC tumor microenvironment at the primary site, elevated CD68+ TAMs and intra-islet CD4+ TILs in omental metastases serve as negative prognostic markers in advanced EOC and imply an unfavorable outcome.

Targeting the IRE1α/XBP1 Endoplasmic Reticulum Stress Response Pathway in ARID1A -Mutant Ovarian Cancers

Abstract The SWI/SNF chromatin-remodeling complex is frequently altered in human cancers. For example, the SWI/SNF component ARID1A is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), for which effective treatments are lacking. Here, we report that ARID1A transcriptionally represses the IRE1α–XBP1 axis of the endoplasmic reticulum (ER) stress response, which confers sensitivity to inhibition of the IRE1α–XBP1 pathway in ARID1A-mutant OCCC. ARID1A mutational status correlated with response to inhibition of the IRE1α–XBP1 pathway. In a conditional Arid1aflox/flox/Pik3caH1047R genetic mouse model, Xbp1 knockout significantly improved survival of mice bearing OCCCs. Furthermore, the IRE1α inhibitor B-I09 suppressed the growth of ARID1A-inactivated OCCCs in vivo in orthotopic xenograft, patient-derived xenograft, and the genetic mouse models. Finally, B-I09 synergized with inhibition of HDAC6, a known regulator of the ER stress response, in suppressing the growth of ARID1A-inactivated OCCCs. These studies define the IRE1α−XBP1 axis of the ER stress response as a targetable vulnerability for ARID1A-mutant OCCCs, revealing a promising therapeutic approach for treating ARID1A-mutant ovarian cancers. Significance: These findings indicate that pharmacological inhibition of the IRE1α–XBP1 pathway alone or in combination with HDAC6 inhibition represents an urgently needed therapeutic strategy for ARID1A-mutant ovarian cancers.

Expression Profiles Reveal Involvement of VEGF, IGF1, BIRC5, and MMP1 in Vulvar Carcinogenesis

Objective: The objective of this study was to identify key genes and shed light on the underlying molecular mechanisms of vulvar squamous cell carcinoma (VSCC). Methods: Bioinformatic software was utilized for the identification and characterization of key differentially expressed genes (DEGs) from microarrays GSE63678 and GSE38228, which contain VSCC and normal vulvar tissue data. These microarrays were obtained from Gene Expression Omnibus (GEO). Immunohistochemical assays (55 VSCC and 50 normal vulvar tissues) were utilized to validate the expression of VEGF, IGF1, BIRC5, and MMP1 screened from the identified DEGs. SPSS 18.0 software was used for statistical analyses of the relationships between IGF1, BIRC5, VEGF, MMP1 expression levels and patient clinicopathological characteristics. Results: A total of 141 DEGs were identified, among which 18 genes were closely correlated with the biological characteristics of VSCC. Four of the 18 genes ( VEGF, IGF1, BIRC5, and MMP1) screened from the GEO database were markedly enriched in pathways in cancer ( P < 0.05), and could be considered key genes in VSCC based on KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis in DAVID (Database for Annotation, Visualization and Integrated Discovery).The expression levels of these 4 hub genes, determined by immunohistochemical assays, were consistent with the bioinformatics results. Higher expression of IGF1 showed significant association with well-differentiated carcinomas ( P = 0.017). BIRC5 expression levels showed a positive correlation with clinical stage ( P = 0.039); compared with those in menopause for over 10 years, patients in menopause for less than 10 years at the time of diagnosis tended to have significantly higher expression of BIRC5 ( P = 0.003). VEGF and MMP1 expression levels were not correlated with any of the tested clinicopathological characteristics. Conclusion: VEGF, IGF1, BIRC5, and MMP1 were identified as being associated with VSCC using integrated bioinformatic methods, which may provide important insights into the pathogenesis of this disease and help to identify new biomarkers.

Combined delivery of salinomycin and docetaxel by dual-targeting gelatinase nanoparticles effectively inhibits cervical cancer cells and cancer stem cells

Intra-tumor heterogeneity is widely accepted as one of the key factors, which hinders cancer patients from achieving full recovery. Especially, cancer stem cells (CSCs) may exhibit self-renewal capacity, which makes it harder for complete elimination of tumor. Therefore, simultaneously inhibiting CSCs and non-CSCs in tumors becomes a promising strategy to obtain sustainable anticancer efficacy. Salinomycin (Sal) was reported to be critical to inhibit CSCs. However, the poor bioavailability and catastrophic side effects brought about limitations to clinical practice. To solve this problem, we previously constructed gelatinase-stimuli nanoparticles composed of nontoxic, biocompatible polyethylene glycol-polycaprolactone (PEG-PCL) copolymer with a gelatinase-cleavable peptide Pro-Val-Gly-Leu-Iso-Gly (PVGLIG) inserted between the two blocks of the copolymer. By applying our "smart" gelatinase-responsive nanoparticles for Sal delivery, we have demonstrated specific accumulation in tumor, anti-CSCs ability and reduced toxicity of Sal-NPs in our previous study. In the present study, we synthesized Sal-Docetaxel-loaded gelatinase-stimuli nanoparticles (Sal-Doc NP) and confirmed single emulsion as the optimal method of producing Sal-Doc NPs (Sal-Doc SE-NP) in comparison with nanoprecipitation. Sal-Doc SE-NPs inhibited both CSCs and non-CSCs in mice transplanted with cervical cancer, and might be associated with enhanced restriction of epithelial-mesenchymal transition (EMT) pathway. Besides, the tumorigenic capacity and growing speed were obviously suppressed in Sal-Doc-SE-NPs-treated group in rechallenge experiment. Our results suggest that Sal-Doc-loaded gelatinase-stimuli nanoparticles could be a promising strategy to enhance antitumor efficacy and reduce side effects by simultaneously suppressing CSCs and non-CSCs.

Correlation of immediate prevalence of cervical squamous cell precancers and cancers with HPV genotype and age in women with LSIL cytology: A retrospective analysis of 1617 cases

AbstractAimsTo evaluate the immediate risk of cervical squamous cell precancers and cancers in women with low‐grade squamous intraepithelial lesion (LSIL) cytology according to different high‐risk human papillomavirus (hrHPV) results and age stratification.MethodsThe study included 1617 women with LSIL cytology and underwent simultaneous Aptima HPV genotyping (E6/E7 mRNA test) followed by cervical biopsy.ResultsAmong 1317 hrHPV positive cases, other 11 types of hrHPV were the most frequent (68.8%), followed by HPV16 (11.1%), HPV18/45 (4.1%), and HPV16/HPV18/45 (0.5%). Compared to other groups, HPV18/45 positive group and other 11 types of hrHPV group showed significantly higher prevalence of intraepithelial neoplasia grade (CIN)1 (p < .0001), while HPV16 positive and HPV16/HPV18/45 dual positive groups showed significantly higher prevalence of CIN2/3 (p < .0001). In addition, hrHPV positive, 25–39 years‐old age group showed a significantly higher prevalence of CIN1 (p = .032) than the other age groups. Furthermore, CIN1 prevalence was significantly higher in patients under 40 or 50 years of age than in those over 40 or 50 years of age (p = .005 and p = .011, respectively). However, there was no significant difference among the different age groups in CIN2/3 prevalence in women with LSIL cytology.ConclusionIn southern Chinese women population, LSIL cytology carries very low immediate risk of high‐grade squamous intraepithelial lesions (HSIL) (CIN2/3) in general. However, HPV16 positive and HPV16/HPV18/45 dual positive indicated a higher immediate risk of high‐grade squamous intraepithelial lesions (HSIL) (CIN2/3). Age is not an immediate risk factor in this patient population for high‐grade squamous lesions or SCC. These results are similar to data from cytology laboratories in the United States and other international settings, therefore strongly support the usage of ASCCP guidelines in this patient population.