Epithelial Ovarian Cancer is infiltrated by activated effector T cells co-expressing CD39, PD-1, TIM-3, CD137 and interacting with cancer cells and myeloid cells

Introduction: Despite predicted efficacy, immunotherapy in epithelial ovarian cancer (EOC) has limited clinical benefit and the prognosis of patients remains poor. There is thus a strong need for better identifying local immune dynamics and immune-suppressive pathways limiting T-cell mediated anti-tumor immunity. Methods: In this observational study we analyzed by immunohistochemistry, gene expression profiling and flow cytometry the antigenic landscape and immune composition of 48 EOC specimens, with a focus on tumor-infiltrating lymphocytes (TILs). Results: Activated T cells showing features of partial exhaustion with a CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ surface profile were exclusively present in EOC specimens but not in corresponding peripheral blood or ascitic fluid, indicating that the tumor microenvironment might sustain this peculiar phenotype. Interestingly, while neoplastic cells expressed several tumor-associated antigens possibly able to stimulate tumor-specific TILs, macrophages provided both co-stimulatory and inhibitory signals and were more abundant in TILs-enriched specimens harboring the CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ signature. Conclusions: These data demonstrate that EOC is enriched in CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ T lymphocytes, a phenotype possibly modulated by antigen recognition on neoplastic cells and by a combination of inhibitory and co-stimulatory signals largely provided by infiltrating myeloid cells. Furthermore, we have identified immunosuppressive pathways potentially hampering local immunity which might be targeted by immunotherapeutic approaches 46 samples derived from epithelial ovarian cancer patients were analyzed

引言：尽管免疫治疗在上皮性卵巢癌（epithelial ovarian cancer, EOC）中被预测具有疗效，但其临床获益仍有限，患者预后依旧不佳。因此，亟需更精准地解析限制T细胞介导抗肿瘤免疫的局部免疫动态与免疫抑制通路。
方法：本项观察性研究采用免疫组化（immunohistochemistry）、基因表达谱分析（gene expression profiling）及流式细胞术（flow cytometry），对48份上皮性卵巢癌标本的抗原谱与免疫组成进行了分析，重点关注肿瘤浸润淋巴细胞（tumor-infiltrating lymphocytes, TILs）。
结果：呈现部分耗竭特征、且具有CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+表面表型的活化T细胞，仅存在于上皮性卵巢癌标本中，而非对应的外周血或腹水，这提示肿瘤微环境可能维持这种特殊的细胞表型。值得注意的是，尽管肿瘤细胞可表达多种能够刺激肿瘤特异性TIL的肿瘤相关抗原，但巨噬细胞同时提供共刺激与抑制信号，且在携带该表型特征且TIL富集的标本中更为丰富。
结论：本研究数据证实，上皮性卵巢癌中富集CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ T淋巴细胞，该表型可能受肿瘤细胞的抗原识别以及浸润髓系细胞提供的抑制与共刺激信号联合调控。此外，本研究还鉴定出可能阻碍局部免疫的免疫抑制通路，此类通路或可作为免疫治疗的潜在靶点。本研究共分析了46份源自上皮性卵巢癌患者的标本。