Distinct immune characteristics and differential anti-PD-1-mediated reinvigoration potential of CD8+ TILs based on BRCA1/2 mutation status in epithelial ovarian cancer.

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    • Abstract:
      Objective: We aimed to discover the different immunological properties of tumor immune microenvironment in epithelial ovarian cancer (EOC) according to BRCA1/2 mutations (BRCA1/2muts) status and differential programmed cell death protein 1 (PD-1) expression levels. Methods: Tumor-infiltrating lymphocytes (TILs) were collected from patients with newly diagnosed advanced-stage EOC (Yonsei University Health System [YUHS] cohort, n = 117). This YUHS cohort was compared with The Cancer Genome Atlas data for ovarian serous cystadenocarcinoma (n=482), in terms of survival outcomes and immune-related gene profiles according to BRCA1/2 status. We used multicolor flow cytometry to characterize the immune phenotypes and heterogeneity of TILs with or without BRCA1/2muts. In vitro functional assays were conducted to evaluate the reinvigorating ability of CD8+ TILs upon anti-PD-1 treatment. Results: We found that EOC patients with BRCA1/2muts exhibited better survival outcomes and significantly higher tumor mutation burden, compared to BRCA1/2 wild type (BRCA1/2wt) patients. Furthermore, CD8+ TILs within BRCA1/2mut tumors displayed characteristics indicating more severe T-cell exhaustion than their BRCA1/2wt counterparts. Notably, the capacity for anti-PD-1- mediated reinvigoration of CD8+ TILs was significantly greater in BRCA1/2wt tumors compared to BRCA1/2mut tumors. Additionally, within the BRCA1/2wt group, the frequency of PD-1high CD8+ TILs was positively correlated with the reinvigoration capacity of CD8+ TILs after anti-PD-1 treatment. Conclusion: Our results highlight unique immune features of CD8+ TILs in EOC and a differential response to anti-PD-1 treatment, contingent upon BRCA1/2mut status. These findings suggest that immune checkpoint blockade may be a promising frontline therapeutic option for selected BRCA1/2wt EOC patients. [ABSTRACT FROM AUTHOR]
    • Abstract:
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