There is a need for better classification and understanding of tumor-infiltrating lymphocytes (TILs). Here, we applied advanced functional genomics to interrogate 9,000 human tumors and multiple single-cell sequencing sets using benchmarked T cell states, comprehensive T cell differentiation trajectories, human and mouse vaccine responses, and other human TILs. Compared with other T cell states, enrichment of T memory/resident memory programs was observed across solid tumors. Trajectory analysis of single-cell melanoma CD8⁺ TILs also identified a high fraction of memory/resident memory-scoring TILs in anti-PD-1 responders, which expanded post therapy. In contrast, TILs scoring highly for early T cell activation, but not exhaustion, associated with non-response. Late/persistent, but not early activation signatures, prognosticate melanoma survival, and co-express with dendritic cell and IFN-γ response programs. These data identify an activation-like state associated to poor response and suggest successful memory conversion, above resuscitation of exhaustion, is an under-appreciated aspect of successful anti-tumoral immunity.

需要更好地分类和理解肿瘤浸润淋巴细胞（TIL）。在这里，我们应用先进的功能基因组学，使用基准 T 细胞状态、全面的 T 细胞分化轨迹、人类和小鼠疫苗反应以及其他人类 TIL 来询问 9,000 个人类肿瘤和多个单细胞测序集。与其他 T 细胞状态相比，在实体瘤中观察到 T 记忆/驻留记忆程序的丰富。单细胞黑色素瘤 CD8 ⁺ TIL 的轨迹分析还发现，抗 PD-1 应答者中有很高比例的记忆/常驻记忆评分 TIL，且在治疗后会扩大。相比之下，TIL 在早期 T 细胞激活方面得分较高，但在与无反应相关的衰竭方面得分较低。晚期/持续而非早期的激活特征可预测黑色素瘤的存活，并与树突状细胞和 IFN-γ 反应程序共表达。这些数据确定了与不良反应相关的类激活状态，并表明成功的记忆转换（高于疲劳复苏）是成功抗肿瘤免疫的一个未被充分认识的方面。