Somatic mutations in tumor-infiltrating lymphocytes impact on antitumor immunity

Fumiaki Mukohara, Kazuma Iwata, takamasa ishino, Takashi Inozume, Joji Nagasaki, Youki Ueda, Ken Suzawa, Toshihide Ueno, Hideki Ikeda, Katsushige Kawase, Yuka Saeki, Shusuke Kawashima, Kazuo Yamashita, Yu Kawahara, Yasuhiro Nakamura, Akiko Honobe-Tabuchi, Hiroko Watanabe, Hiromichi Dansako, Tatsuyoshi Kawamura, Yutaka SuzukiHiroaki Honda, Hiroyuki Mano, Shinichi Toyooka, Masahito Kawazu, Yosuke Togashi

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Article numbere2320189121
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number35
DOIs
Publication statusPublished - Aug 27 2024

Keywords

  • T cell
  • cancer immunology
  • somatic mutation
  • tumor-infiltrating lymphocytes

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Somatic mutations in tumor-infiltrating lymphocytes impact on antitumor immunity'. Together they form a unique fingerprint.

Cite this