A burned-out CD8+ T-cell subset expands in the tumor microenvironment and curbs cancer immunotherapy. A burned-out CD8+ T-cell subset expands in the tumor microenvironment and curbs cancer immunotherapy

Tumor-infiltrating lymphocytes (TILs) are considered to be exhausted, lacking proliferative and effector functions, which impairs cancer immunity. We employed single-cell mass cytometry and tissue imaging technologies to dissect TILs in 25 resectable and 35 advanced non-small cell lung cancer (NSCLC) patients. We identified a phenotypically burn-out CD8 TIL subset (Ebo), specifically accumulated within the tumor microenvironment (TME). In contrast to exhausted T-cells, Ebo appears to be the most proliferative TIL subset. Furthermore, Ebo showed the highest expression of activation markers, but it was more apoptotic and produced less IFNg than other CD8 TIL subsets. Using a humanized patient-derived tumor xenograft model, we demonstrated that Ebo expansion occurred within the TME in a PD-pathway dependent manner. Importantly, Ebo abundance in baseline tumor tissues was associated with resistance to anti-PD therapy in NSCLC patients. Our study identified a dysfunctional TIL subset, distinct from exhausted T-cells, and implies strategies to overcome resistance in cancer immunotherapy. Overall design: There are 3 groups, 3 samples in each group, overall 9 samples analyzed

肿瘤浸润淋巴细胞（Tumor-infiltrating lymphocytes, TILs）通常被认为处于耗竭状态，丧失增殖与效应功能，进而削弱机体抗肿瘤免疫能力。本研究采用单细胞质谱流式细胞技术与组织成像技术，对25例可切除非小细胞肺癌（non-small cell lung cancer, NSCLC）患者及35例晚期非小细胞肺癌患者的肿瘤浸润淋巴细胞进行解析。研究团队鉴定出一类表型疲态型CD8阳性肿瘤浸润淋巴细胞亚群（Ebo），该亚群特异性富集于肿瘤微环境（tumor microenvironment, TME）中。与耗竭T细胞不同，Ebo亚群是增殖能力最强的肿瘤浸润淋巴细胞亚群。此外，Ebo亚群的激活标志物表达水平最高，但相较于其他CD8阳性肿瘤浸润淋巴细胞亚群，其凋亡率更高，且分泌的γ干扰素（IFNγ）水平显著更低。通过人源化患者来源肿瘤异种移植模型，本研究证实Ebo亚群的扩增发生于肿瘤微环境内，且依赖于PD通路。值得注意的是，基线肿瘤组织中Ebo亚群的丰度与非小细胞肺癌患者对抗PD治疗的耐药性显著相关。本研究鉴定出一类区别于耗竭T细胞的功能异常肿瘤浸润淋巴细胞亚群，其研究结果为破解肿瘤免疫治疗耐药性提供了潜在策略。整体实验设计：本研究共设置3组，每组包含3份样本，总计9份样本纳入分析。