Somatic mutations in tumor-infiltrating lymphocytes impact on antitumor immunity

• Published in: Proceedings of the National Academy of Sciences Vol. 121; no. 35; p. e2320189121
• Main Authors: Mukohara, Fumiaki, Iwata, Kazuma, Ishino, Takamasa, Inozume, Takashi, Nagasaki, Joji, Ueda, Youki, Suzawa, Ken, Ueno, Toshihide, Ikeda, Hideki, Kawase, Katsushige, Saeki, Yuka, Kawashima, Shusuke, Yamashita, Kazuo, Kawahara, Yu, Nakamura, Yasuhiro, Honobe-Tabuchi, Akiko, Watanabe, Hiroko, Dansako, Hiromichi, Kawamura, Tatsuyoshi, Suzuki, Yutaka, Honda, Hiroaki, Mano, Hiroyuki, Toyooka, Shinichi, Kawazu, Masahito, Togashi, Yosuke
• Format: Journal Article
• Language: English
• Published: United States Proceedings of the National Academy of Sciences 27.08.2024; National Academy of Sciences
• Subjects: Animals; Anticancer properties; Antitumor activity; Biological Sciences; Biomarkers; Cancer; CD3 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Clonal deletion; Cloning; Female; Frameshift mutation; Gene deletion; Gene sequencing; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunity; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Melanoma; Melanoma - genetics; Melanoma - immunology; Mice; Mice, Knockout; Mutation; PD-1 protein; Phenotypes; Therapeutic targets; Tumor Necrosis Factor alpha-Induced Protein 3 - genetics; Tumor-infiltrating lymphocytes; Whole genome sequencing; tumor-infiltrating lymphocytes; somatic mutation; T cell; cancer immunology
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2320189121

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.