Somatic mutations in tumor-infiltrating lymphocytes impact on antitumor immunity.

Abstract

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 <i>SH2D2A</i> loss-of-function frameshift mutation and <i>TNFAIP3</i> deletion could activate T cell effector functions in vitro. Furthermore, we generated CD8⁺ T cell-specific <i>Tnfaip3</i> knockout mice and showed that <i>Tnfaip3</i> 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 <i>SH2D2A</i> 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.