Nagasaki et al. showed that a resected melanoma of an anti-PD-1 non-responder patient exhibited diverse TCR clonotypes. Two complete-responder patients had skewed TCR clonotypes, with Tex cells (expressing exhaustion-associated genes), but not Tnon-ex cells being tumor-specific. PD-1 blockade led to expansion, revitalization, and infiltration of T cells that expressed pre-existing and newly emerged clonotypes and cytolysis genes. Paired TILs and tumor-draining LNs, but only rare PBLs from three patients with other solid cancers had Tex cells and tumor-specific clonotypes. Mouse tumor models recapitulated these findings.
Contributed by Paula Hochman
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.
Author Info: (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, Explorator
Author Info: (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) KOTAI Biotechnologies, Inc., Osaka 565-0871, Japan. (6) KOTAI Biotechnologies, Inc., Osaka 565-0871, Japan. (7) Division of Cellular Signaling, National Cancer Center, Research Institute, Tokyo 104-0045, Japan. (8) Division of Cellular Signaling, National Cancer Center, Research Institute, Tokyo 104-0045, Japan. (9) 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. (10) Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan. (11) Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan. (12) Department of Dermatology, University of Yamanashi, Chuo, Japan. (13) Department of Dermatology, University of Yamanashi, Chuo, Japan. (14) Department of Thoracic Surgery, Chiba Cancer Center, Chiba 260-8717, Japan. (15) Department of Thoracic Surgery, Chiba Cancer Center, Chiba 260-8717, Japan. (16) 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. (17) Department of Head and Neck Surgery, Chiba Cancer Center, Chiba 260-8717, Japan. (18) Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan. (19) Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. (20) Department of Dermatology, University of Yamanashi, Chuo, Japan. (21) Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan. (22) Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan. (23) Division of Cellular Signaling, National Cancer Center, Research Institute, Tokyo 104-0045, Japan. (24) Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8568, Japan. (25) 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. (26) 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.
