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

Shogo Kumagai; Yosuke Togashi; Takahiro Kamada; Eri Sugiyama; Hitomi Nishinakamura; Yoshiko Takeuchi; Kochin Vitaly; Kota Itahashi; Yuka Maeda; Shigeyuki Matsui; Takuma Shibahara; Yasuho Yamashita; Takuma Irie; Ayaka Tsuge; Shota Fukuoka; Akihito Kawazoe; Hibiki Udagawa; Keisuke Kirita; Keiju Aokage; Genichiro Ishii; Takeshi Kuwata; Kenta Nakama; Masahito Kawazu; Toshihide Ueno; Naoya Yamazaki; Koichi Goto; Masahiro Tsuboi; Hiroyuki Mano; Toshihiko Doi; Kohei Shitara; Hiroyoshi Nishikawa

doi:10.1038/s41590-020-0769-3

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

Nat Immunol. 2020 Nov;21(11):1346-1358. doi: 10.1038/s41590-020-0769-3. Epub 2020 Aug 31.

Authors

Shogo Kumagai^#^{1

2}, Yosuke Togashi^#¹, Takahiro Kamada^#^{1

2}, Eri Sugiyama^{1

2}, Hitomi Nishinakamura¹, Yoshiko Takeuchi¹, Kochin Vitaly², Kota Itahashi¹, Yuka Maeda¹, Shigeyuki Matsui³, Takuma Shibahara⁴, Yasuho Yamashita⁴, Takuma Irie¹, Ayaka Tsuge^{1

2}, Shota Fukuoka¹, Akihito Kawazoe⁵, Hibiki Udagawa⁶, Keisuke Kirita⁶, Keiju Aokage⁷, Genichiro Ishii⁸, Takeshi Kuwata⁸, Kenta Nakama⁹, Masahito Kawazu¹⁰, Toshihide Ueno¹⁰, Naoya Yamazaki⁹, Koichi Goto⁶, Masahiro Tsuboi⁷, Hiroyuki Mano¹⁰, Toshihiko Doi⁵, Kohei Shitara⁵, Hiroyoshi Nishikawa^{11

12}

Affiliations

¹ Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan.
² Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³ Department of Biostatics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁴ Research and Development Group, Hitachi Ltd., Tokyo, Japan.
⁵ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
⁶ Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
⁷ Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
⁸ Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan.
⁹ Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹⁰ Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
¹¹ Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Chiba, Japan. hnishika@ncc.go.jp.
¹² Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. hnishika@ncc.go.jp.

^# Contributed equally.

PMID: 32868929
DOI: 10.1038/s41590-020-0769-3

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens / chemistry
Antigens / immunology
Biomarkers, Tumor
CD28 Antigens / metabolism
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Gene Expression Regulation / drug effects*
Humans
Immune Checkpoint Inhibitors / pharmacology*
Immune Checkpoint Inhibitors / therapeutic use
Immunomodulation
Lymphocyte Activation / immunology
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism
Molecular Targeted Therapy
Neoplasm Metastasis
Neoplasm Staging
Neoplasms / drug therapy
Neoplasms / etiology
Neoplasms / metabolism
Neoplasms / mortality
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
Signal Transduction
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism*
Treatment Outcome
Tumor Microenvironment / immunology

Substances

Antigens
Biomarkers, Tumor
CD28 Antigens
Immune Checkpoint Inhibitors
Peptides
Programmed Cell Death 1 Receptor
Reactive Oxygen Species
Receptors, Antigen, T-Cell