我们的目的是根据 BRCA1/2 突变状态和差异 PD-1 表达水平来研究上皮性卵巢癌 (EOC) 肿瘤免疫微环境的独特免疫学特征。从新诊断的晚期患者中收集肿瘤浸润淋巴细胞 (TIL) -阶段 EOC（YUHS 队列，n=117）。该 YUHS 队列与卵巢浆液性囊腺癌 (n=482) 的癌症基因组图谱 (TCGA) 数据进行了比较，比较了生存结果和根据 BRCA1/2 状态的免疫相关基因谱。我们使用多色流式细胞术来表征有或没有 BRCA1/2 突变的 TIL 的免疫表型和异质性。我们进行了体外功能测定，以评估 CD8 TIL 对抗 PD-1 治疗的重振能力。我们发现，具有 BRCA1/2 突变 (BRCA1/2mt) 的 EOC 患者表现出更好的生存结果和显着更高的肿瘤突变负荷 (TMB) ，与 BRCA1/2 非突变 (BRCA1/2wt) 患者相比。此外，BRCA1/2mt 肿瘤内的 CD8 TIL 表现出的特征表明，比 BRCA1/2wt 肿瘤中的 T 细胞耗竭更严重。值得注意的是，与 BRCA1/2mt 肿瘤相比，BRCA1/2wt 肿瘤中抗 PD-1 介导的 CD8 TIL 重振能力显着更强。此外，在 BRCA1/2wt 组中，PD-1highCD8 TIL 的频率与抗 PD-1 治疗后 CD8 TIL 的恢复能力呈正相关。我们的结果强调了 EOC 中 CD8 TIL 的独特免疫特征以及对 EOC 的差异反应。抗 PD-1 治疗，取决于 BRCA1/2 突变状态。这些发现表明，对于选定的 BRCA1/2wt EOC 患者，免疫检查点阻断可能是一种有前景的一线治疗选择。© 作者（或其雇主）2024。CC BY-NC 允许重复使用。不得商业再利用。请参阅权利和权限。英国医学杂志出版。

We aimed to investigate the distinct immunological characteristics of the tumor immune microenvironment in epithelial ovarian cancer (EOC) according to BRCA1/2 mutations status and differential PD-1 expression levels.Tumor-infiltrating lymphocytes (TILs) were collected from patients with newly diagnosed advanced-stage EOC (YUHS cohort, n=117). This YUHS cohort was compared with The Cancer Genome Atlas (TCGA) 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 BRCA1/2 mutations. In vitro functional assays were conducted to evaluate the reinvigorating ability of CD8+ TILs on anti-PD-1 treatment.We found that EOC patients with BRCA1/2 mutations (BRCA1/2mt) exhibited better survival outcomes and significantly higher tumor mutation burden (TMB), compared with BRCA1/2 non-mutated (BRCA1/2wt) patients. Furthermore, CD8+ TILs within BRCA1/2mt 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 with BRCA1/2mt tumors. Additionally, within the BRCA1/2wt group, the frequency of PD-1highCD8+ TILs was positively correlated with the reinvigoration capacity of CD8+ TILs after anti-PD-1 treatment.Our results highlight unique immune features of CD8+ TILs in EOC and a differential response to anti-PD-1 treatment, contingent on BRCA1/2 mutation status. These findings suggest that immune checkpoint blockade may be a promising frontline therapeutic option for selected BRCA1/2wt EOC patients.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.