Dataset Information

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer.

ABSTRACT: Importance:Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective:To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design, Setting, and Participants:This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24?650 person-years. Exposures:Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (?20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures:Overall survival time. Results:The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend?=?4.2?×?10?16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form. Conclusions and Relevance:This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

SUBMITTER: Ovarian Tumor Tissue Analysis (OTTA) Consortium

PROVIDER: S-EPMC5744673 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer.

Goode Ellen L EL Block Matthew S MS Kalli Kimberly R KR Vierkant Robert A RA Chen Wenqian W Fogarty Zachary C ZC Gentry-Maharaj Aleksandra A Tołoczko Aleksandra A Hein Alexander A Bouligny Aliecia L AL Jensen Allan A Osorio Ana A Hartkopf Andreas A Ryan Andy A Chudecka-Głaz Anita A Magliocco Anthony M AM Hartmann Arndt A Jung Audrey Y AY Gao Bo B Hernandez Brenda Y BY Fridley Brooke L BL McCauley Bryan M BM Kennedy Catherine J CJ Wang Chen C Karpinskyj Chloe C de Sousa Christiani B CB Tiezzi Daniel G DG Wachter David L DL Herpel Esther E Taran Florin Andrei FA Modugno Francesmary F Nelson Gregg G Lubiński Jan J Menkiszak Janusz J Alsop Jennifer J Lester Jenny J García-Donas Jesús J Nation Jill J Hung Jillian Palacios José J Rothstein Joseph H JH Kelley Joseph L JL de Andrade Jurandyr M JM Robles-Díaz Luis L Intermaggio Maria P MP Widschwendter Martin M Beckmann Matthias W MW Ruebner Matthias M Jimenez-Linan Mercedes M Singh Naveena N Oszurek Oleg O Harnett Paul R PR Rambau Peter F PF Sinn Peter P Wagner Philipp P Ghatage Prafull P Sharma Raghwa R Edwards Robert P RP Ness Roberta B RB Orsulic Sandra S Brucker Sara Y SY Johnatty Sharon E SE Longacre Teri A TA Ursula Eilber E McGuire Valerie V Sieh Weiva W Natanzon Yanina Y Li Zheng Z Whittemore Alice S AS Anna deFazio A Staebler Annette A Karlan Beth Y BY Gilks Blake B Bowtell David D DD Høgdall Estrid E Candido dos Reis Francisco J FJ Steed Helen H Campbell Ian G IG Gronwald Jacek J Benítez Javier J Koziak Jennifer M JM Chang-Claude Jenny J Moysich Kirsten B KB Kelemen Linda E LE Cook Linda S LS Goodman Marc T MT García María José MJ Fasching Peter A PA Kommoss Stefan S Deen Suha S Kjaer Susanne K SK Menon Usha U Brenton James D JD Pharoah Paul DP PDP Chenevix-Trench Georgia G Huntsman David G DG Winham Stacey J SJ Köbel Martin M Ramus Susan J SJ

JAMA oncology 20171201 12

<h4>Importance</h4>Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.<h4>Objective</h4>To define the prognostic role of CD8+ TILs in epithelial ovarian cancer.<h4>Design, setting, and participants</h4>This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consorti ...[more]

PMID: 29049607

Similar Datasets

Project description:Background The 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. Methods We 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). Results This 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). Conclusion This 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 registration https://www.crd.york.ac.uk/prospero/, identifier CRD42022366411.

Project description:Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of cancer patients. Although many potential tumor antigens have been described, identifying relevant targets when designing anti-cancer vaccines or targeted cell therapies remains a challenge. To identify novel, potentially immunogenic candidate tumor antigens, we performed integrated tumor transcriptomic, seromic, and proteomic analyses of high grade serous ovarian cancer (HGSC) patient tumor samples. We identified tumor neo-antigens and over-expressed antigens using whole exome and RNA sequencing and examined these in relation to patient-matched auto-antibody repertoires. Focusing on MHC class I epitopes recognized by CD8+ T cells, HLA-binding epitopes were identified or predicted from the highly expressed, mutated, or auto-antibody target antigen, or MHC-associated peptides (MAPs). Recognition of candidate antigenic peptides was assessed within the tumor-infiltrating T lymphocyte (TIL) population expanded from each patient. Known tumor-associated antigens (TAA) and cancer/testis antigens (CTA) were commonly found in the auto-antibody and MAP repertoires and CD8+ TILs recognizing epitopes from these antigens were detected, although neither expression level nor the presence of auto-antibodies correlated with TIL recognition. Auto-antibodies against tumor-mutated antigens were found in most patients, however, no TIL recognition of the highest predicted affinity neo-epitopes was detected. Using high expression level, auto-antibody recognition, and epitope prediction algorithms, we identified epitopes in 5 novel antigens (MOB1A, SOCS3, TUBB, PRKAR1A, CCDC6) recognized by HGSC patient TILs. Furthermore, selection of epitopes from the MAP repertoire identified 5 additional targets commonly recognized by multiple patient TILs. We find that the repertoire of TIL specificities includes recognition of highly expressed and immunogenic self-antigens that are processed and presented by tumors. These results indicate an ongoing autoimmune response against a range of self-antigens targeted by HGSC TILs.

Dataset Information

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer.

Publications

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets