Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments.

Abstract

The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.

• Authors: Shogo Kumagai, Shohei Koyama, Kota Itahashi, Tokiyoshi Tanegashima, Yi-Tzu Lin, Yosuke Togashi, Takahiro Kamada, Takuma Irie, Genki Okumura, Hidetoshi Kono, Daisuke Ito, Rika Fujii, Sho Watanabe, Atsuo Sai, Shota Fukuoka, Eri Sugiyama, Go Watanabe, Takuya Owari, Hitomi Nishinakamura, Daisuke Sugiyama, Yuka Maeda, Akihito Kawazoe, Hiroki Yukami, Keigo Chida, Yuuki Ohara, Tatsuya Yoshida, Yuki Shinno, Yuki Takeyasu, Masayuki Shirasawa, Kenta Nakama, Keiju Aokage, Jun Suzuki, Genichiro Ishii, Takeshi Kuwata, Naoya Sakamoto, Masahito Kawazu, Toshihide Ueno, Taisuke Mori, Naoya Yamazaki, Masahiro Tsuboi, Yasushi Yatabe, Takahiro Kinoshita, Toshihiko Doi, Kohei Shitara, Hiroyuki Mano, Hiroyoshi Nishikawa
• Journal: Cancer cell (Cancer Cell) Vol. 40 Issue 2 Pg. 201-218.e9 (02 14 2022) ISSN: 1878-3686 [Electronic] United States
• PMID: 35090594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Immune Checkpoint Inhibitors
• Immune Checkpoint Proteins
• Programmed Cell Death 1 Receptor
• Lactic Acid

Topics

• Animals
• Biomarkers, Tumor
• CD8-Positive T-Lymphocytes (immunology, metabolism, pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Fluorescent Antibody Technique
• Gene Expression Regulation, Neoplastic (drug effects)
• Glycolysis
• Humans
• Immune Checkpoint Inhibitors (pharmacology, therapeutic use)
• Immune Checkpoint Proteins (metabolism)
• Immunophenotyping
• Lactic Acid (metabolism, pharmacology)
• Lymphocyte Activation
• Lymphocyte Count
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism, pathology)
• Mice
• Molecular Targeted Therapy
• Prognosis
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, genetics, metabolism)
• T-Lymphocytes, Regulatory (drug effects, immunology, metabolism)
• Treatment Outcome
• Tumor Microenvironment (drug effects, genetics)