Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment
Wenhao Zhou,
Shusuke Kawashima,
Takamasa Ishino,
Katsushige Kawase,
Youki Ueda,
Kazuo Yamashita,
Tomofumi Watanabe,
Masahito Kawazu,
Hiromichi Dansako,
Yutaka Suzuki,
Hiroyoshi Nishikawa,
Takashi Inozume,
Joji Nagasaki,
Yosuke Togashi
Affiliations
Wenhao Zhou
Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Department of Urology Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
Shusuke Kawashima
Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Chiba Cancer Center, Research Institute, Division of Cell Therapy, Chiba 260-8717, Japan
Takamasa Ishino
Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; Chiba Cancer Center, Research Institute, Division of Cell Therapy, Chiba 260-8717, Japan; Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Katsushige Kawase
Chiba Cancer Center, Research Institute, Division of Cell Therapy, Chiba 260-8717, Japan; Department of Otorhinolaryngology/Head & Neck Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Youki Ueda
Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
Kazuo Yamashita
KOTAI Biotechnologies, Inc. Osaka 565-0871, Japan
Tomofumi Watanabe
Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-0932, Japan
Masahito Kawazu
Chiba Cancer Center, Research Institute, Division of Cell Therapy, Chiba 260-8717, Japan
Hiromichi Dansako
Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
Yutaka Suzuki
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Kashiwa 277-8568, Japan
Hiroyoshi Nishikawa
Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Division of Cancer Immunology, National Cancer Center, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), Tokyo 104-0045, Kashiwa 277-8577, Japan
Takashi Inozume
Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Chiba Cancer Center, Research Institute, Division of Cell Therapy, Chiba 260-8717, Japan
Joji Nagasaki
Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; Chiba Cancer Center, Research Institute, Division of Cell Therapy, Chiba 260-8717, Japan; Corresponding author
Yosuke Togashi
Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; Chiba Cancer Center, Research Institute, Division of Cell Therapy, Chiba 260-8717, Japan; Division of Cancer Immunology, National Cancer Center, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), Tokyo 104-0045, Kashiwa 277-8577, Japan; Corresponding author
Summary: Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces CD4+ follicular helper T (TFH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the TFH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells.
