The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies

• Published in: Nature immunology Vol. 21; no. 11; pp. 1346 - 1358
• Main Authors: Kumagai, Shogo, Togashi, Yosuke, Kamada, Takahiro, Sugiyama, Eri, Nishinakamura, Hitomi, Takeuchi, Yoshiko, Vitaly, Kochin, Itahashi, Kota, Maeda, Yuka, Matsui, Shigeyuki, Shibahara, Takuma, Yamashita, Yasuho, Irie, Takuma, Tsuge, Ayaka, Fukuoka, Shota, Kawazoe, Akihito, Udagawa, Hibiki, Kirita, Keisuke, Aokage, Keiju, Ishii, Genichiro, Kuwata, Takeshi, Nakama, Kenta, Kawazu, Masahito, Ueno, Toshihide, Yamazaki, Naoya, Goto, Koichi, Tsuboi, Masahiro, Mano, Hiroyuki, Doi, Toshihiko, Shitara, Kohei, Nishikawa, Hiroyoshi
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2020; Nature Publishing Group
• Subjects: 631/250/580; 631/67/580; Antigens - chemistry; Antigens - immunology; Apoptosis; Biomarkers; Biomarkers, Tumor; Biomedical and Life Sciences; Biomedicine; CD28 Antigens - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell death; Cellular proteins; Effector cells; Enzymes; Gene expression; Gene Expression Regulation - drug effects; Genetic aspects; Health aspects; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunology; Immunomodulation; Immunoregulation; Immunosuppression; Immunotherapy; Infectious Diseases; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Staging; Neoplasms - drug therapy; Neoplasms - etiology; Neoplasms - metabolism; Neoplasms - mortality; PD-1 protein; PD-L1 protein; Peptides - chemistry; Peptides - immunology; Prognosis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; Reactive Oxygen Species - metabolism; Receptors, Antigen, T-Cell - metabolism; Regulation; Signal Transduction; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Treatment Outcome; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors; Japan
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-020-0769-3

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. Checkpoint blockade is effective in only a subset of patients; therefore, biomarkers that can predict efficacy would be clinically highly valuable. Nishkawa and colleagues develop a biomarker based on PD-1 positivity of effector and regulatory T cells in the tumor microenvironment that accurately predicts the effectiveness of checkpoint blockade in patients.