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. 2022 Feb 14;40(2):201-218.e9.
doi: 10.1016/j.ccell.2022.01.001. Epub 2022 Jan 28.

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

Shogo Kumagai  1 , Shohei Koyama  2 , Kota Itahashi  3 , Tokiyoshi Tanegashima  3 , Yi-Tzu Lin  4 , Yosuke Togashi  3 , Takahiro Kamada  3 , Takuma Irie  3 , Genki Okumura  3 , Hidetoshi Kono  3 , Daisuke Ito  3 , Rika Fujii  3 , Sho Watanabe  3 , Atsuo Sai  4 , Shota Fukuoka  3 , Eri Sugiyama  3 , Go Watanabe  3 , Takuya Owari  3 , Hitomi Nishinakamura  3 , Daisuke Sugiyama  5 , Yuka Maeda  3 , Akihito Kawazoe  6 , Hiroki Yukami  6 , Keigo Chida  6 , Yuuki Ohara  7 , Tatsuya Yoshida  8 , Yuki Shinno  8 , Yuki Takeyasu  8 , Masayuki Shirasawa  8 , Kenta Nakama  9 , Keiju Aokage  10 , Jun Suzuki  10 , Genichiro Ishii  7 , Takeshi Kuwata  7 , Naoya Sakamoto  7 , Masahito Kawazu  11 , Toshihide Ueno  11 , Taisuke Mori  12 , Naoya Yamazaki  9 , Masahiro Tsuboi  10 , Yasushi Yatabe  12 , Takahiro Kinoshita  13 , Toshihiko Doi  6 , Kohei Shitara  6 , Hiroyuki Mano  11 , Hiroyoshi Nishikawa  14
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Free article

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

Shogo Kumagai et al. Cancer Cell. .
Free article

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.

Keywords: MYC; PD-1; lactic acid; liver metastasis; regulatory T cell.

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Conflict of interest statement

Declaration of interests H.Nishikawa received research funding from Ono Pharmaceutical for this work, research funding and honoraria from Chugai Pharmaceutical, Bristol-Myers Squibb and MSD, honoraria from Ono Pharmaceutical, and research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma, and BD Japan outside of this study. H.Nishikawa is the primary inventor on pending patents PCT/JP2020/0059919 belonging to the National Cancer Center Japan and BD Biosciences. S.Koyama received research funding from Ono Pharmaceutical and Bristol-Myers Squibb outside this study. Y.Togashi received research grants from KOTAI Biotechnologies Inc., Daiichi-Sankyo, Ono Pharmaceutical, Bristol-Myers Squibb, and honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, Chugai Pharmaceutical, and MSD outside of this study. T.Yoshida received grants from Ono Pharmaceutical, AstraZeneca, AMGEN, Daiichi Sankyo, Bristol-Myers Squibb, MSD, Abbvie, and Takeda, and personal fees from Ono Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, MSD, Takeda, Chugai, Novartis, Lilly, Taiho, Archer DX, and Roche outside of this study. K.S. received paid consulting or advisory roles for Astellas, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono, MSD, Taiho, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, and Boehringer Ingelheim; honoraria from Novartis, AbbVie, and Yakult; and research funding from Astellas, Lilly, Ono Pharmaceutical, Sumoitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD, Medi Science, and Eisai outside of this study. Y.S. received research funding from Ono Pharmaceutical and Janssen Pharma and personal fees from AstraZeneca, Chugai, and Pfizer. N.Y. received personal fees from Ono Pharmaceutical, grants from Bristol-Myers Squibb, grants and personal fees from Novartis Pharma K.K., outside the submitted work. All other authors declare no competing financial interests.

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