Department of Dermatology, Weill Cornell Medicine, New York, NY 10026, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, NY 10026, USA.
Institute for Computational Biomedicine, Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
Cancer Cell. 2022 May 9;40(5):524-544.e5. doi: 10.1016/j.ccell.2022.04.005.
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.
需要更好地对肿瘤浸润淋巴细胞 (TIL) 进行分类和理解。在这里，我们应用先进的功能基因组学，使用经过基准测试的 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，对 9000 个人类肿瘤和多个单细胞测序集进行了检测。与其他 T 细胞状态相比，在实体瘤中观察到 T 记忆/常驻记忆程序的富集。单细胞黑色素瘤 CD8 TIL 的轨迹分析也在抗 PD-1 反应者中鉴定出了高比例的记忆/常驻记忆评分 TIL，这些 TIL 在治疗后扩增。相比之下，评分高的 TIL 具有早期 T 细胞激活，但没有衰竭，与无反应相关。晚期/持续性而非早期激活特征预示着黑色素瘤的生存，并与树突状细胞和 IFN-γ 反应程序共同表达。这些数据确定了与不良反应相关的激活样状态，并表明成功的记忆转化，而不是衰竭的复苏，是抗肿瘤免疫中一个未被充分认识的方面。
