Immune checkpoint inhibitors (ICIs) exert clinical efficacy against various types of cancers by reinvigorating exhausted CD8 + T cells that can expand and directly attack cancer cells (cancer-specific T cells) among tumor-infiltrating lymphocytes (TILs). Although some reports have identified somatic mutations in TILs, their effect on antitumor immunity remains unclear. In this study, we successfully established 18 cancer-specific T cell clones, which have an exhaustion phenotype, from the TILs of four patients with melanoma. We conducted whole-genome sequencing for these T cell clones and identified various somatic mutations in them with high clonality. Among the somatic mutations, an SH2D2A loss-of-function frameshift mutation and TNFAIP3 deletion could activate T cell effector functions in vitro. Furthermore, we generated CD8 + T cell–specific Tnfaip3 knockout mice and showed that Tnfaip3 function loss in CD8 + T cell increased antitumor immunity, leading to remarkable response to PD-1 blockade in vivo. In addition, we analyzed bulk CD3 + T cells from TILs in additional 12 patients and identified an SH2D2A mutation in one patient through amplicon sequencing. These findings suggest that somatic mutations in TILs can affect antitumor immunity and suggest unique biomarkers and therapeutic targets.

中文翻译：

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肿瘤浸润淋巴细胞的体细胞突变影响抗肿瘤免疫


免疫检查点抑制剂 (ICIs) 通过恢复耗尽的 CD8 发挥临床功效，对抗各种类型的癌症+肿瘤浸润淋巴细胞 (TIL) 中能够扩增并直接攻击癌细胞（癌症特异性 T 细胞）的 T 细胞。尽管一些报告已经鉴定出 TIL 的体细胞突变，但它们对抗肿瘤免疫的影响仍不清楚。在这项研究中，我们从四名黑色素瘤患者的 TIL 中成功建立了 18 个具有衰竭表型的癌症特异性 T 细胞克隆。我们对这些 T 细胞克隆进行了全基因组测序，并鉴定了其中具有高克隆性的各种体细胞突变。在体细胞突变中， SH2D2A功能丧失移码突变和TNFAIP3缺失可以在体外激活T细胞效应功能。此外，我们生成了 CD8 + T细胞特异性Tnfaip3敲除小鼠并表明Tnfaip3 CD8 功能丧失+ T细胞增加了抗肿瘤免疫力，导致体内对PD-1阻断产生显着反应。此外，我们还分析了批量 CD3 +来自另外 12 名患者的 TIL 的 T 细胞，并鉴定出SH2D2A通过扩增子测序发现一名患者发生突变。这些发现表明 TIL 中的体细胞突变可以影响抗肿瘤免疫，并提出独特的生物标志物和治疗靶点。