In a cohort of gastric and non-small cell lung cancer patients treated with anti-PD-1, responding patients had higher PD-1 expression on tumor-infiltrating CD8+ T cells and reduced PD-1 on effector Tregs. PD-1 expression on CD8+ T cells correlated with exposure to higher-affinity antigens. Anti-PD-1 mAb activated both PD-1+ Tregs and CD8+ T cells by restoring CD3/CD28 signaling and downstream ZAP70/AKT phosphorylation. The relative expression of PD-1 on CD8+ T cells and Tregs regulated proliferation in co-culture and tumor progression in vivo, and could predict anti-PD-1 patient responders better than prior biomarkers (AUC 0.933).
Contributed by Alex Najibi
ABSTRACT: Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1(+)CD8(+) T cells relative to that of PD-1(+) regulatory T (T(reg)) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8(+) T cells and T(reg) cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1(+)CD8(+) T cells and enhanced PD-1(+) T(reg) cell-mediated immunosuppression. A profound reactivation of effector PD-1(+)CD8(+) T cells rather than PD-1(+) T(reg) cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.
Author Info: (1) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. Department of Immun
Author Info: (1) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (2) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. (3) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (4) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (5) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. (6) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. (7) Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (8) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. (9) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. (10) Department of Biostatics, Nagoya University Graduate School of Medicine, Nagoya, Japan. (11) Research and Development Group, Hitachi Ltd., Tokyo, Japan. (12) Research and Development Group, Hitachi Ltd., Tokyo, Japan. (13) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. (14) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (15) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. (16) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. (17) Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. (18) Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. (19) Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan. (20) Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan. (21) Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan. (22) Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. (23) Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. (24) Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. (25) Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. (26) Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. (27) Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan. (28) Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. (29) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. (30) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. (31) Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. hnishika@ncc.go.jp. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. hnishika@ncc.go.jp.
