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Prognostic impact of tumor-infiltrating lymphocytes in high grade serous ovarian cancer: a systematic review and meta-analysis.

ABSTRACT: Background:Tumor-infiltrating lymphocytes (TILs) are involved in the antitumor immune response. The association between prognosis in patients with TILs and high-grade serous ovarian cancer (HGSOC) remains obscure, with some studies reporting conflicting results. Methods:We conducted an extensive literature search of electronic databases and retrieved prognostic data of each selected subtype of TILs, including CD3+, CD4+, CD8+, CD103+, and PD-1+ TILs. The fixed-effects model was applied to derive the pooled hazard ratio (HR) and 95% confidence interval (CI) of these markers. Results:The systematic review process yielded 19 eligible studies comprising 6004 patients with HGSOC. We compared TIL-positive and TIL-negative patients, and the pooled HRs from the multivariate analysis revealed that intraepithelial CD8+ TILs were positively correlated with progression-free survival (PFS, HR 0.46, 95% CI 0.25-0.67) and overall survival (OS, HR 0.90, 95% CI 0.86-0.9); stromal CD8+ TILs were positively correlated with OS (HR 0.61, 95% CI 0.36-0.87). Furthermore, the pooled HRs from univariate analysis demonstrated that intraepithelial CD3+, CD4+, CD8+, and CD103+ TILs were positively associated with OS (HR 0.58, 95% CI 0.44-0.72; HR 0.37, 95% CI 0.16-0.59; HR 0.51, 95% CI 0.42-0.60, and HR 0.59, 95% CI 0.44-0.74, respectively); stromal CD4+ and CD8+ TILs were significantly associated with OS (HR 0.63, 95% CI 0.32-0.94 and HR 0.78, 95% CI 0.58-0.97, respectively). However, the pooled HR from the multivariate analysis revealed that PD-1+ TILs were not associated with the OS of patients with HGSOC (HR 0.97, 95% CI 0.90-1.04). Conclusion:This meta-analysis provided evidence of the association of CD3+, CD4+, CD8+, and CD103+ TILs with the survival benefits (OS and PFS) of patients with HGSOC.

SUBMITTER: Hao J

PROVIDER: S-EPMC7607723 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Prognostic impact of tumor-infiltrating lymphocytes in high grade serous ovarian cancer: a systematic review and meta-analysis.

Hao Jiatao J Yu Hui H Yu Hui H Zhang Taohong T An Ruifang R Xue Yan Y

Therapeutic advances in medical oncology 20201031

<h4>Background</h4>Tumor-infiltrating lymphocytes (TILs) are involved in the antitumor immune response. The association between prognosis in patients with TILs and high-grade serous ovarian cancer (HGSOC) remains obscure, with some studies reporting conflicting results.<h4>Methods</h4>We conducted an extensive literature search of electronic databases and retrieved prognostic data of each selected subtype of TILs, including CD3+, CD4+, CD8+, CD103+, and PD-1+ TILs. The fixed-effects model was ap ...[more]

PMID: 33193829

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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: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.

Dataset Information

Prognostic impact of tumor-infiltrating lymphocytes in high grade serous ovarian cancer: a systematic review and meta-analysis.

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Prognostic impact of tumor-infiltrating lymphocytes in high grade serous ovarian cancer: a systematic review and meta-analysis.

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