PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes

Joji Nagasaki¹, Takashi Inozume², Nicolas Sax³, Ryo Ariyasu⁴, Masakazu Ishikawa³, Kazuo Yamashita³, Masahito Kawazu⁵, Toshihide Ueno⁵, Takuma Irie⁴, Etsuko Tanji⁶, Takao Morinaga⁶, Akiko Honobe⁷, Takehiro Ohnuma⁷, Mitsuru Yoshino⁸, Takekazu Iwata⁸, Katsushige Kawase⁹, Keita Sasaki¹⁰, Toyoyuki Hanazawa¹¹, Vitaly Kochin¹², Tatsuyoshi Kawamura⁷, Hiroyuki Matsue¹³, Masayuki Hino¹⁴, Hiroyuki Mano⁵, Yutaka Suzuki¹⁵, Hiroyoshi Nishikawa¹⁶, Yosuke Togashi¹⁷

Affiliations

¹ Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan; Division of Cancer Immunology, National Cancer Center, Research Institute, Exploratory Oncology Research and Clinical Trial Center (EPOC), 6-5-1 Kashiwanoha, Tokyo 104-0045, Kashiwa 277-8577, Japan; Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
² Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan; Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Department of Dermatology, University of Yamanashi, Chuo, Japan.
³ KOTAI Biotechnologies, Inc., Osaka 565-0871, Japan.
⁴ Division of Cancer Immunology, National Cancer Center, Research Institute, Exploratory Oncology Research and Clinical Trial Center (EPOC), 6-5-1 Kashiwanoha, Tokyo 104-0045, Kashiwa 277-8577, Japan.
⁵ Division of Cellular Signaling, National Cancer Center, Research Institute, Tokyo 104-0045, Japan.
⁶ Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan.
⁷ Department of Dermatology, University of Yamanashi, Chuo, Japan.
⁸ Department of Thoracic Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.
⁹ Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan; Department of Head and Neck Surgery, Chiba Cancer Center, Chiba 260-8717, Japan; Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
¹⁰ Department of Head and Neck Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.
¹¹ Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
¹² Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
¹³ Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
¹⁴ Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
¹⁵ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8568, Japan.
¹⁶ Division of Cancer Immunology, National Cancer Center, Research Institute, Exploratory Oncology Research and Clinical Trial Center (EPOC), 6-5-1 Kashiwanoha, Tokyo 104-0045, Kashiwa 277-8577, Japan; Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: hnishika@ncc.go.jp.
¹⁷ Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan; Division of Cancer Immunology, National Cancer Center, Research Institute, Exploratory Oncology Research and Clinical Trial Center (EPOC), 6-5-1 Kashiwanoha, Tokyo 104-0045, Kashiwa 277-8577, Japan; Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-0932, Japan. Electronic address: ytogashi1584@gmail.com.

PMID: 35108529
DOI: 10.1016/j.celrep.2022.110331

Free article

PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes

Joji Nagasaki et al. Cell Rep. 2022.

Free article

. 2022 Feb 1;38(5):110331.

doi: 10.1016/j.celrep.2022.110331.

Authors

Affiliations

¹ Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan; Division of Cancer Immunology, National Cancer Center, Research Institute, Exploratory Oncology Research and Clinical Trial Center (EPOC), 6-5-1 Kashiwanoha, Tokyo 104-0045, Kashiwa 277-8577, Japan; Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
² Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan; Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Department of Dermatology, University of Yamanashi, Chuo, Japan.
³ KOTAI Biotechnologies, Inc., Osaka 565-0871, Japan.
⁴ Division of Cancer Immunology, National Cancer Center, Research Institute, Exploratory Oncology Research and Clinical Trial Center (EPOC), 6-5-1 Kashiwanoha, Tokyo 104-0045, Kashiwa 277-8577, Japan.
⁵ Division of Cellular Signaling, National Cancer Center, Research Institute, Tokyo 104-0045, Japan.
⁶ Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan.
⁷ Department of Dermatology, University of Yamanashi, Chuo, Japan.
⁸ Department of Thoracic Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.
⁹ Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan; Department of Head and Neck Surgery, Chiba Cancer Center, Chiba 260-8717, Japan; Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
¹⁰ Department of Head and Neck Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.
¹¹ Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
¹² Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
¹³ Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
¹⁴ Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
¹⁵ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8568, Japan.
¹⁶ Division of Cancer Immunology, National Cancer Center, Research Institute, Exploratory Oncology Research and Clinical Trial Center (EPOC), 6-5-1 Kashiwanoha, Tokyo 104-0045, Kashiwa 277-8577, Japan; Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: hnishika@ncc.go.jp.
¹⁷ Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan; Division of Cancer Immunology, National Cancer Center, Research Institute, Exploratory Oncology Research and Clinical Trial Center (EPOC), 6-5-1 Kashiwanoha, Tokyo 104-0045, Kashiwa 277-8577, Japan; Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-0932, Japan. Electronic address: ytogashi1584@gmail.com.

PMID: 35108529
DOI: 10.1016/j.celrep.2022.110331

Abstract

PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (T_ex) or nonexhaustion signatures (T_non-ex). Among skewed clonotypes, those in the T_ex, but not those in the T_non-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the T_ex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such T_ex clonotypes, mainly from TDLNs.

Keywords: PD-1 blockade therapy; exhausted T cell; neoantigen; single-cell RNA sequencing; single-cell TCR sequencing; tumor microenvironment; tumor-draining lymph node; tumor-specific T cell.

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Conflict of interest statement

Declaration of interests N.S., M.I., and K.Y. are employees of KOTAI Biotechnologies Inc. T.I. received honoraria and research grants from Ono Pharmaceutical, Bristol-Myers Squibb, and MSD outside of this study. T.H. received a research grant from Ono Pharmaceutical outside of this study. H. Mano received a research grant from Ono Pharmaceutical outside of this study. H.N. received honoraria and research funding from Ono Pharmaceutical, Chugai Pharmaceutical, MSD and Bristol-Myers Squibb, and research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharm, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma, and BD Japan outside of this study. Y.T. received a research grant from KOTAI Biotechnologies Inc. related to this study. Y.T. also received research grants and honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, and Daiichi-Sankyo, and honoraria from AstraZeneca, Chugai Pharmaceutical, and MSD outside of this study. All other authors declare no competing interests.

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PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes

Affiliations

PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes

Authors

Affiliations

Abstract

Conflict of interest statement

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