Somatic mutations in tumor-infiltrating lymphocytes impact on antitumor immunity
Immune checkpoint inhibitors (ICIs) exert clinical efficacy against various types of cancers by reinvigorating exhausted CD8<sup>+</sup> 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<sup>+</sup> T cell-specific <i>Tnfaip3</i> knockout mice and showed that <i>Tnfaip3</i> function loss in CD8<sup>+</sup> T cell increased antitumor immunity, leading to remarkable response to PD-1 blockade in vivo. In addition, we analyzed bulk CD3<sup>+</sup> 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.
Authors
- Hideki Ikeda (ORCID: https://orcid.org/0009-0000-1334-7597)
- Takamasa Ishino (ORCID: https://orcid.org/0000-0002-8601-0677)
- Katsushige Kawase (ORCID: https://orcid.org/0000-0001-6998-8481)
- Shinichi Toyooka (ORCID: https://orcid.org/0000-0002-7588-6745)
- Hiroaki Honda (ORCID: https://orcid.org/0000-0002-4617-9670)
- Kazuo Yamashita (ORCID: https://orcid.org/0000-0002-7825-4719)
- Masahito Kawazu
- Yosuke Togashi (ORCID: https://orcid.org/0000-0001-9910-0164)
- Yu Kawahara (ORCID: https://orcid.org/0009-0007-1190-4872)
- Hiromichi Dansako (ORCID: https://orcid.org/0000-0002-2353-3024)
- Takashi Inozume (ORCID: https://orcid.org/0000-0001-7054-1863)
- Youki Ueda (ORCID: https://orcid.org/0000-0002-2627-8524)
- Ken Suzawa (ORCID: https://orcid.org/0000-0003-2463-9696)
- Tatsuyoshi Kawamura (ORCID: https://orcid.org/0000-0003-4008-2322)
- Yutaka Suzuki (ORCID: https://orcid.org/0000-0003-4852-1879)
- Fumiaki Mukohara
- Toshihide Ueno (ORCID: https://orcid.org/0000-0002-7408-7298)
- Shusuke Kawashima (ORCID: https://orcid.org/0000-0001-6628-4331)
- Kazuma Iwata
- Joji Nagasaki (ORCID: https://orcid.org/0000-0003-0945-5469)
- Yasuhiro Nakamura (ORCID: https://orcid.org/0000-0002-3664-5818)
- Akiko Honobe‐Tabuchi (ORCID: https://orcid.org/0009-0006-8649-847X)
- Hiroyuki Mano (ORCID: https://orcid.org/0000-0003-4645-0181)
- Hiroko Watanabe
- Yuka Saeki (ORCID: https://orcid.org/0009-0008-0120-6664)
Institutions
- Chiba University (JP)
- Okayama University (JP)
- Chiba Cancer Center (JP)
- Tokyo Women's Medical University (JP)
- University of Yamanashi (JP)
- The University of Tokyo (JP)
- Saitama Medical University (JP)
- Kindai University (JP)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1073/pnas.2320189121
- Citations
- 4
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.13
Funders
- Naito Foundation
- Takeda Science Foundation
- Japan Agency for Medical Research and Development
- Astellas Pharma
- Astellas Foundation for Research on Metabolic Disorders
- Princess Takamatsu Cancer Research Fund
- MSD Life Science Foundation, Public Interest Incorporated Foundation
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology
- ACT-X
- Moonshot Research and Development Program