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

 January 28, 2022
National Cancer Center Japan
Nagoya University
Japan Agency for Medical Research and Development
in Japanese

Highlights

• Lactic acid (LA) induces PD-1 expression by Treg cells in highly glycolytic tumors.
• LA absorbed through MCT1 is a metabolic checkpoint of immune responses.
• MYC expression accelerates glycolysis and promotes PD-1 expression by Treg cells.
• MCT1 highly expressed by Treg cells, provides therapeutic target for immunotherapy.

Summary

High PD-1 expression by Treg cells in the tumor microenvironment (TME) is a resistant mechanism for PD-1 blockade therapy. Treg cells harbor higher PD-1 expression compared to effector T cells in highly glycolytic tumors including MYC-amplified tumors and liver tumors. Mechanistically, under low-glucose environments, tumors release a large amount of LA that is taken up by Treg cells through MCT1, the expression of which is controlled by FOXP3 and promotes NFAT1 translocation into the nucleus, resulting in enhanced PD-1 expression by Treg cells but not effector T cells. Kumagai et al. propose a novel mechanism of PD-1 expression by Treg cells induced by LA through MCT1 in highly glycolytic tumors, thereby playing an active role in the impairment of antitumor immunity and the resistance to PD-1 blockade therapy.

Publication

Journal name

Cancer cell

Title

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

Authors

Shogo Kumagai, Shohei Koyama, Kota Itahashi, Tokiyoshi Tanegashima, Yi-tzu Lin, Yosuke Togashi, Takahiro Kamada, Takuma Irie, Genki Okumura, Hidetoshi Kohno, 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 and Hiroyoshi Nishikawa

DOI

doi: 10.1016/j.ccell.2022.01.001.

URL

https://www.sciencedirect.com/science/article/pii/S1535610822000034 (link to external site)

Publication date

Available online 28 January 2022

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