Ex Vivo Immuno-Oncology Platform Reveals Spatial T Cell Infiltration Patterns Linked to ATR Inhibition Responses in High-Grade Serous Ovarian Cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE307725 | GEO | 2025/09/15
REPOSITORIES: GEO
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Project description:Ex Vivo Immuno-Oncology Platform Reveals Spatial T Cell Infiltration Patterns Linked to ATR Inhibition Responses in High-Grade Serous Ovarian Cancer
| PRJNA1327215 | ENA
Project description:The goal of this experiment was to generate scRNA-seq data for human HGSC cells and human FTE cells. FTE is the progenitor cell type for HGSC.
2020-06-15 | GSE150864 | GEO
Project description:The broad research use of organoids from high-grade serous ovarian carcinoma (HGSC) has been hampered by low culture success rates and limited availability of fresh tumor material. Here we describe a method for generation and long-term expansion of HGSC organoids with efficacy markedly improved over previous reports (53% vs. 23-38%). We established organoids from cryopreserved material, demonstrating the feasibility of using viably biobanked tissue for HGSC organoid derivation. Genomic, histologic and single-cell transcriptomic analyses revealed that organoids recapitulated genetic and phenotypic features of original tumors. Organoid drug responses correlated with clinical treatment outcomes, although in culture conditions-dependent manner and only in organoids maintained in human plasma-like medium (HPLM). Organoids from consenting patients are available to the research community through a public biobank and organoid genomic data explorable through an interactive online tool. Taken together, this resource facilitates the application of HGSC organoids in basic and translational ovarian cancer research.
2023-04-03 | GSE202263 | GEO
Project description:Despite immunotherapy's promise in cancer treatment, patient responses vary substantially because of the individual nature of the immune system and the lack of reliable biomarkers. To address this issue, we developed a precision ex vivo platform that integrates patient-specific tumor and immune cells to study the mechanisms of antitumor immune response, predict immunotherapy outcomes, and identify effective treatments. This platform revealed unique single-cell immune response mechanisms and sensitivities to standard-of-care immunotherapies. Furthermore, we were able to identify a synergistic combination of anti-programmed cell death protein 1 (anti-PD-1) together with a Casitas B lineage lymphoma-b inhibitor that overcame anti-PD-1 resistance in selected patient samples. Activation of the interferon-γ-stimulated cytokines predicted combination efficacy, while immunosuppressive cytokines were associated with poor response. Our findings underscore the platform's potential in tailoring immunotherapies and advancing drug development, offering avenues for personalized cancer treatment.
| S-EPMC11524168 | biostudies-literature
Project description:Background: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. Methods: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature which we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TILs), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Results: Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N=715 new set, HR 1.65, 95% CI 1.10-2.46, p=0.015; N=325 published set HR 2.87, 95% CI 2.17-3.81, p=2.2 x 10-13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N=599, HR 2.22, 95% CI 1.66-2.95, p=4.1 x 10-8). Methylation signature was inversely related to CD8+ TIL levels (p=2.4 x 10-7) and TAP1 expression (p=0.0011) and was associated with gene expression molecular subtype (p=5.9 x 10-4) in covariate-adjusted analysis. Conclusions: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.
2023-02-22 | GSE223467 | GEO
Project description:Background: The aim of this study was to identify differentially expressed miRNAs in high-grade serous ovarian carcinoma (HGSC), clear cell ovarian carcinoma (CCC) and ovarian surface epithelium (OSE). Selected miRNAs were evaluated for association with clinical parameters including survival, and miRNA/mRNA interactions were mapped. Results: Differentially expressed miRNAs between HGSC, CCC and OSE were identified, of which 18 were validated (p<0.01) using RT-qPCR in an extended cohort. Compared with OSE, miR-205-5p was the most overexpressed miRNA in HGSC. miR-200 family members and miR-182-5p were the most overexpressed in HGSC and CCC compared with OSE, whereas miR-383 was the most underexpressed. miR-509-3-5p, miR-509-5p, miR-509-3p and miR-510 were among the strongest differentiators between HGSC and CCC, all being significantly overexpressed in CCC compared with HGSC. High miR-200c-3p expression was associated with poor progression-free (p=0.031) and overall (p=0.026) survival in HGSC. Interacting miRNAs and mRNA targets, including those of a TP53-related pathway presented previously, were identified in HGSC. Conclusions: Several miRNAs are overexpressed in HGSC and CCC compared with OSE, including the miR-200 family, among which miR-200c-3p is associated with survival in HGSC. A set of miRNAs differentiates CCC from HGSC, of which miR-509-3-5p and miR-509-5p are the strongest classifiers. Several interactions between miRNAs and mRNAs in HGSC were mapped. Methods: Differences in miRNA expression between HGSC, CCC and OSE scrapings were analyzed by global miRNA expression profiling (Affymetrix GeneChip miRNA 2.0 Arrays, n=30), validated by RT-qPCR (n=63), and evaluated for associations with clinical parameters. For HGSC, differentially expressed miRNAs were linked to differentially expressed mRNAs identified previously (GSE36668).
2014-02-13 | E-GEOD-47841 | biostudies-arrayexpress
Project description:High grade serous ovarian cancers (HGSC) are deadly malignancies that relapse despite carboplatin chemotherapy. Many commercially ovarian cancer cell lines are not good models for HGSC. Here we demonstrate that 3 low passage cell lines derived from HGSC have similar transcriptomes to their parental bulk tumors. These cell lines recapitulated tumor characteristics of the primary cancer and had responded to therapy in the same manner as primary HGSC cells, demonstrating they are accurate models for HGSCs. mRNA profiles of low passage high grade serous tumor cell lines and their parental tumors, generated by next generation sequencing, were compared.
2015-08-01 | E-GEOD-70073 | biostudies-arrayexpress
Project description:Profiling of loss of heterozygosity (LOH) in HGSC, subcrouping HGSC by LOH-based clustering and comparing to the LOH profiles of triple-negative breast cancer [previously submitted; GSE19594]. Study for the correlation of LOH burdern and LOH-based subgroups to clinical response to platinum-based chemotherapy in patients suffered from HGSC. SNP data (Affymetrix GenChip 250K SNP Nsp) from 47 high grade serous ovarian cancer were generated and used for LOH and copy number analysis, LOH-based hierarchical clustering to subclassify HGSC, and comparison to the chromosomal alterations in high grade brest cancer. The associstion between LOH-based subgroups and LOH burden and clinical resposne to platinum-based chemotherapy was investigated. The results were validated in two independent public opening datasets.
2012-11-06 | E-GEOD-39130 | biostudies-arrayexpress
Project description:Cancer immunotherapy, which aims to control the immune system to eradicate cancer cells and prevent their spread, needs to be personalized because anticancer immune responses can be inhibited in several ways that vary from patient to patient. Cancer immunotherapy includes pharmaceuticals such as immune checkpoint inhibitors and monoclonal antibodies (MAbs) as well as cell therapy, immunogene therapy, and vaccines. Combination of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) drugs with other immunotherapy drugs, for example, antibody-drug conjugates, as well as combination of PD-1/PD-L1 drugs with other therapies, for example, chemotherapy and radiation therapy, are being explored. Biomarkers are important for predicting the response to immunotherapy. Molecular diagnostics and sequencing are important technologies for guiding treatment in immuno-oncology. Genomic profiling of tumor mutational burden may enhance the predictive utility of PD-L1 expression and facilitate personalized combination immunotherapy. Optimization of personalized immuno-oncology requires integration of several technologies and selection of those best suited for an individual patient. Advances in immuno-oncology are also attributed to technologies for targeted delivery of anticancer therapeutics such as antigen-capturing nanoparticles for precision targeting and selective delivery. A breakthrough in cell therapy of cancer is a chimeric antigen receptors-T cell, which combines the antigen-binding site of a MAb with the signal activating machinery of a T cell, freeing antigen recognition from major histocompatibility complex restriction. Gene-editing tools such as clustered regularly interspaced short palindromic repeats have a promising application for removing alloreactivity and decreasing immunogenicity of third-party T cells. In conclusion, personalized immuno-oncology is one of the most promising approaches to management of cancer.
| S-EPMC7923844 | biostudies-literature
Project description:Organotypic tumor slices represent a physiologically-relevant culture system for studying the tumor microenvironment. Systematic characterization of the tumor slice culture system will enable its effective application for translational research. Here, using flow cytometry-based immunophenotyping, we performed a comprehensive characterization of the immune cell composition in organotypic tumor slices prepared from four syngeneic mouse tumor models and a human liver tumor. We found that the immune cell compositions of organotypic tumor slices prepared on the same day as the tumor cores were harvested are similar. Differences were primarily observed in the lymphocyte population of a clinical hepatocellular carcinoma case. Viable populations of immune cells persisted in the tumor slices for 7 days. Despite some changes in the immune cell populations, we showed the utility of mouse tumor slices for assessing responses to immune-modulatory agents. Further, we demonstrated the ability to use patient-derived xenograft tumor slices for assessing responses to targeted and cytotoxic drugs. Overall, tumor slices provide a broadly useful platform for studying the tumor microenvironment and evaluating the preclinical efficacy of cancer therapeutics.
| S-EPMC6844320 | biostudies-literature