Shaping Immune Responses in the Tumor Microenvironment of Ovarian Cancer.
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ABSTRACT:
SUBMITTER: Luo X
PROVIDER: S-EPMC8261131 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ovarian cancer is the leading cause of death among gynecological neoplasms, with an estimated 14,000 deaths in 2019. First-line treatment options center around a taxane and platinum-based chemotherapy regimen. However, many patients often have recurrence due to late stage diagnoses and acquired chemo-resistance. Recent approvals for bevacizumab and poly (ADP-ribose) polymerase inhibitors have improved treatment options but effective treatments are still limited in the recurrent setting. Immunotherapy has seen significant success in hematological and solid malignancies. However, effectiveness has been limited in ovarian cancer. This may be due to a highly immunosuppressive tumor microenvironment and a lack of tumor-specific antigens. Certain immune cell subsets, such as regulatory T cells and tumor-associated macrophages, have been implicated in ovarian cancer. Consequently, therapies augmenting the immune response, such as immune checkpoint inhibitors and dendritic cell vaccines, may be unable to properly enact their effector functions. A better understanding of the various interactions among immune cell subsets in the peritoneal microenvironment is necessary to develop efficacious therapies. This review will discuss various cell subsets in the ovarian tumor microenvironment, current immunotherapy modalities to target or augment these immune subsets, and treatment challenges.
| S-EPMC7843421 | biostudies-literature
Project description:Women with endometriosis are at increased risk of developing ovarian cancer, specifically ovarian endometrioid, low-grade serous, and clear-cell adenocarcinoma. An important clinical caveat to the association of endometriosis with ovarian cancer is the improved prognosis for women with endometriosis at time of ovarian cancer staging. Whether endometriosis-associated ovarian cancers develop from the molecular transformation of endometriosis or develop because of the endometriotic tumor microenvironment remain unknown. Additionally, how the presence of endometriosis improves prognosis is also undefined, but likely relies on the endometriotic microenvironment. The unique tumor microenvironment of endometriosis is composed of epithelial, stromal, and immune cells, which adapt to survive in hypoxic conditions with high levels of iron, estrogen, and inflammatory cytokines and chemokines. Understanding the unique molecular features of the endometriotic tumor microenvironment may lead to impactful precision therapies and/or modalities for prevention. A challenge to this important study is the rarity of well-characterized clinical samples and the limited model systems. In this review, we will describe the unique molecular features of endometriosis-associated ovarian cancers, the endometriotic tumor microenvironment, and available model systems for endometriosis-associated ovarian cancers. Continued research on these unique ovarian cancers may lead to improved prevention and treatment options.
| S-EPMC6115869 | biostudies-other
Project description:ObjectiveTo explore the regulatory role of miR-4772 in the formation of tumor immune microenvironment in ovarian cancer.MethodsThe optimal cutoff level of PD-L1 expression was calculated based on data from 294 ovarian cancer patients in the TCGA database. The differentially expressed genes (DEGs) between high and low PD-L1 expression groups were screened, and the important DEGs were identified by correlation analysis. WGCNA analysis was performed to select the weighted genes and PD-L1-related miRNAs, from which the hub genes were obtained by intersection analysis. ssGSEA analysis was used to evaluate the effect of PD-L1 and miR-4772 expressions on the tumor immune microenvironment in ovarian cancer. KEGG analysis was used to identify the involved signal pathways, and the interactions between the hub genes were mapped by protein-protein interaction (PPI) analysis. Survival analysis was carried out to identify the survival-related hub genes, and the results were validated using the data of 399 patients with ovarian cancer from GEO database and the sequencing results of SKOV3 cells transfected with miR-4772 mimics or inhibitor.ResultsAccording the optimal cutoff level of PD-L1 expression of 1.31582 (90th quantile), the patients were divided into high- and low-PD-L1 expression groups. A total of 840 DEGs were identified, including 549 significantly up-regulated genes and 291 down-regulated genes. Among them, 20 important DEGs were found to closely correlate with miR-4772 expression, and WGCNA analysis identified 48 weighted genes significantly correlated with miR-4772. Twelve genes were identified as both key DEGs and weighted genes and were treated as the hub genes. ssGSEA analysis showed that both the patients with high PD-L1 expressions and those with high miR-4772 expressions showed more active immune infiltration and functional activity. The 12 hub genes were involved mainly in immune-related signaling pathways, and PPI analysis suggested significant interactions among the hub genes. The two hub genes CD96 and TBX21 showed close correlation with the survival of ovarian cancer patients. The sequencing results of SKOV3 cells transfected with miR-4772 mimics or inhibitor showed that the changes in miR-4772 expression level caused obvious changes in the expressions of the 12 hub genes and PD-L1.ConclusionMiR-4772 plays a regulatory role in the formation of tumor immune microenvironment in ovarian cancer by regulating 12 hub genes.
| S-EPMC9742773 | biostudies-literature
Project description:It is estimated that in the United States in 2018 there will be 22,240 new cases of ovarian cancer and 14,070 deaths due to this malignancy. The most common subgroup of this disease is high-grade serous ovarian cancer (HGSOC), which is known for its aggressiveness, high recurrence rate, metastasis to other sites, and the development of resistance to conventional therapy. It is important to understand the ovarian cancer tumor microenvironment (TME) from the viewpoint of the function of pre-existing immune cells, as immunocompetent cells are crucial to mounting robust antitumor responses to prevent visible tumor lesions, disease progression, or recurrence. Networks consisting of innate and adaptive immune cells, metabolic pathways, intracellular signaling molecules, and a vast array of soluble factors, shape the pathogenic nature of the TME and are useful prognostic indicators of responses to conventional therapy and immunotherapy, and subsequent survival rates. This review highlights key immune cells and soluble molecules in the TME of ovarian cancer, which are important in the development of effective antitumor immunity, as well as those that impair effector T cell activity. A more insightful knowledge of the HGSOC TME will reveal potential immune biomarkers to aid in the early detection of this disease, as well as biomarkers that may be targeted to advance the design of novel therapies that induce potent antitumor immunity and survival benefit.
| S-EPMC6162424 | biostudies-literature
Project description:Objective: Because of the modest immunotherapeutic response among ovarian carcinoma (OC) patients, it is significant to evaluate antitumor immune response and develop more effective precision immunotherapeutic regimens. Here, this study aimed to determine diverse immune subtypes of OC. Methods: This study curated the expression profiles of prognostic immunologically relevant genes and conducted consensus clustering analyses for determining immune subtypes among OC patients in TCGA cohort. With Boruta algorithm, characteristic genes were screened for conducting an immune scoring system through principal component analysis algorithm. The single-sample gene set enrichment analysis and ESTIAMTE methods were adopted for quantifying the immune infiltrates and responses to chemotherapeutic agents were estimated with pRRophetic algorithm. Two immunotherapeutic cohorts were used for investigating the efficacy of immune score in predicting therapeutic benefits. Results: Two immune subtypes were conducted among 377 OC patients. Immune subtype 2 was characterized by worse clinical prognosis, more frequent genetic variations and mutations, enhanced immune infiltrates, and increased expression of MHC molecules and programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1). In total, 30 prognosis-relevant characteristic immune subtype-derived genes were identified for constructing the immune score of OC patients. High immune score was linked with more dismal prognosis, decreased immune infiltrations, and expression of MHC molecules. High immune score presented favorable sensitivity to doxorubicin and vinorelbine and reduced sensitivity to cisplatin. In addition, immune score possessed the potential in predicting benefits from anti-PD-1/PD-L1 therapy. Conclusion: Collectively, our findings propose two complex and diverse immune subtypes of OC. Quantitative assessment of immune subtypes in individual patients strengthens the understanding of tumor microenvironment features and promotes more effective immunotherapeutic regimens.
| S-EPMC8977982 | biostudies-literature
Project description:BackgroundAccumulating evidence demonstrated that tumor microenvironmental cells played important roles in predicting clinical outcomes and therapeutic efficacy. We aimed to develop a reliable immune-related gene signature for predicting the prognosis of ovarian cancer (OC).MethodsSingle sample gene-set enrichment analysis (ssGSEA) of immune gene-sets was used to quantify the relative abundance of immune cell infiltration and develop high- and low-abundance immune subtypes of 308 OC samples. The presence of infiltrating stromal/immune cells in OC tissues was calculated as an estimate score. We estimated the correlation coefficients among the immune subtype, clinicopathological feature, immune score, distribution of immune cells, and tumor mutation burden (TMB). The differentially expressed immune-related genes between high- and low-abundance immune subtypes were further used to construct a gene signature of a prognostic model in OC with lasso regression analysis.ResultsThe ssGSEA analysis divided OC samples into high- and low-abundance immune subtypes based on the abundance of immune cell infiltration, which was significantly related to the estimate score and clinical characteristics. The distribution of immune cells was also significantly different between high- and low-abundance immune subtypes. The correlation analysis showed the close relationship between TMB and the estimate score. The differentially expressed immune-related genes between high- and low-abundance immune subtypes were enriched in multiple immune-related pathways. Some immune checkpoints (PDL1, PD1, and CTLA-4) were overexpressed in the high-abundance immune subtype. Furthermore, the five-immune-related-gene-signature prognostic model (CCL18, CXCL13, HLA-DOB, HLA-DPB2, and TNFRSF17)-based high-risk and low-risk groups were significantly related to OC overall survival.ConclusionImmune-related genes were the promising predictors of prognosis and survival, and the comprehensive landscape of tumor microenvironmental cells of OC has potential for therapeutic schedule monitoring.
| S-EPMC7928403 | biostudies-literature
Project description:The mortality rate of ovarian cancer (OC) remains the highest among all gynecological malignancies. Platinum-based chemotherapies are effective in treating most OC cases. However, chemoresistance is still a major challenge for successful OC treatments. Emerging evidence has highlighted that the modulation of the tumor immune microenvironment is involved in chemoresistance, but the mechanism remains unclear. This study aimed to investigate whether resistance to cisplatin (CDDP), the standard treatment for OC, is due to the remodeling of the tumor immune microenvironment by the transcription factor EB (TFEB). We hypothesized that TFEB is not essential for tumor survival but is associated with CDDP resistance. We collected 20 tissue samples of OC patients who had not undergone chemotherapy or radiotherapy prior to surgery. We cultured OC cell lines and performed cell transfection and assays as well as analytical, fluorescence microscopy, and immunohistochemical techniques to explore a novel function of TFEB in remodeling the tumor immune microenvironment in OC. We found a positive correlation between TFEB and programmed cell death-ligand 1 (PD-L1), PD-L2, and HLA-A expression in OC cells and tissues. We also found that CDDP treatment induced TFEB nuclear translocation, thus increasing PD-L1 and PD-L2 expression to foster an immunosuppressive tumor microenvironment, which mediates tumor immune evasion and drug resistance. Interestingly, TFEB also regulated HLA-A expression, which increases the tumor immunogenicity of OC. Finally, in a syngenic murine model of OC, we observed the therapeutic benefit of CDDP plus programmed cell death-1 (PD-1) inhibitor, which enhanced the cytolytic activity of CD8+ T cells and inhibited tumor growth. Our study illustrates the important role of TFEB in regulating the tumor immune microenvironment in OC.
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Project description:Tumor immune infiltration plays a key role in the progression of solid tumors, including ovarian cancer, and immunotherapies are rapidly emerging as effective treatment modalities. However, the role of cancer-associated fibroblasts (CAFs), a predominant stromal constituent, in determining the tumor-immune microenvironment and modulating efficacy of immunotherapies remains poorly understood. We have conducted an extensive bioinformatic analysis of our and other publicly available ovarian cancer datasets (GSE137237, GSE132289 and GSE71340), to determine the correlation of fibroblast subtypes within the tumor microenvironment (TME) with the characteristics of tumor-immune infiltration. We identified (1) four functional modules of CAFs in ovarian cancer that are associated with the TME and metastasis of ovarian cancer, (2) immune-suppressive function of the collagen 1,3,5-expressing CAFs in primary ovarian cancer and omental metastases, and (3) consistent positive correlations between the functional modules of CAFs with anti-immune response genes and negative correlation with pro-immune response genes. Our study identifies a specific fibroblast subtype, fibroblast functional module (FFM)2, in the ovarian cancer tumor microenvironment that can potentially modulate a tumor-promoting immune microenvironment, which may be detrimental toward the effectiveness of ovarian cancer immunotherapies.
| S-EPMC7692816 | biostudies-literature
Project description:The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generate spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes. We identify a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we report a prognostic role of a proliferative tumor-cell subpopulation, which associates with enhanced spatial tumor-immune interactions by CD8+ and CD4 + T-cells in the BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the potential to improve immunotherapeutic strategies and patient stratification in HGSC.
| S-EPMC8837628 | biostudies-literature
Project description:Anti-PD1/PDL1 therapy has proven efficacious against many cancers but only reached modest objective response rates against recurrent ovarian cancer. A deeper understanding of the tumor microenvironment (TME) may reveal other immunosuppressive mechanisms that warrant investigation as immunotherapeutic targets for this challenging disease. Matched primary and recurrent tumors from patients with high-grade serous ovarian carcinoma (HGSC) were analyzed by multicolor immunohistochemistry/immunofluorescence for the presence of T cells, B cells, macrophages, and for the expression of immunosuppressive and HLA molecules. Cancer- and immune-related gene expression was assessed by NanoString analysis. Recurrent tumors showed increased infiltration by immune cells, displayed higher expression of PDL1, IDO, and HLA molecules, and contained more stromal tissue. NanoString analysis demonstrated increased expression of gene signatures related to chemokines and T cell functions in recurrent tumors. The ovarian tumors showed high gene expression of LAG3 and HAVCR2 (TIM3) and enhanced levels of TIGIT and CTLA4 in recurrent tumors compared to primary tumors. The majority of HGSC developed into a more inflamed phenotype during progression from primary to recurrent disease, including indications of adaptive immune resistance. This suggests that recurrent tumors may be particularly sensitive to inhibition of adaptive immune resistance mechanisms.
| S-EPMC7767114 | biostudies-literature