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Somatic mutations in tumor-infiltrating lymphocytes impact on antitumor immunity.
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.
Afiliación
  • Mukohara F; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
  • Iwata K; Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University, Okayama 700-8558, Japan.
  • Ishino T; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
  • Inozume T; Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University, Okayama 700-8558, Japan.
  • Nagasaki J; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
  • Ueda Y; Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
  • Suzawa K; Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
  • Ueno T; Division of Cell Therapy, Chiba Cancer Research Institute, Chiba 260-8717, Japan.
  • Ikeda H; Department of Dermatology, University of Yamanashi, Yamanashi 409-3898, Japan.
  • Kawase K; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
  • Saeki Y; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
  • Kawashima S; Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University, Okayama 700-8558, Japan.
  • Yamashita K; Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
  • Kawahara Y; Division of Cell Therapy, Chiba Cancer Research Institute, Chiba 260-8717, Japan.
  • Nakamura Y; Department of Respiratory Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
  • Honobe-Tabuchi A; Division of Cell Therapy, Chiba Cancer Research Institute, Chiba 260-8717, Japan.
  • Watanabe H; Department of Otorhinolaryngology/Head & Neck Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
  • Dansako H; Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
  • Kawamura T; Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
  • Suzuki Y; Division of Cell Therapy, Chiba Cancer Research Institute, Chiba 260-8717, Japan.
  • Honda H; KOTAI Biotechnologies, Inc., Osaka 565-0871, Japan.
  • Mano H; Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
  • Toyooka S; Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama 350-1298, Japan.
  • Kawazu M; Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama 350-1298, Japan.
  • Togashi Y; Department of Dermatology, University of Yamanashi, Yamanashi 409-3898, Japan.
Proc Natl Acad Sci U S A ; 121(35): e2320189121, 2024 Aug 27.
Article en En | MEDLINE | ID: mdl-39167601
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos Infiltrantes de Tumor / Linfocitos T CD8-positivos / Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa Límite: Animals / Female / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos Infiltrantes de Tumor / Linfocitos T CD8-positivos / Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa Límite: Animals / Female / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Estados Unidos