| Literature DB >> 35090594 |
Shogo Kumagai1, Shohei Koyama2, Kota Itahashi3, Tokiyoshi Tanegashima3, Yi-Tzu Lin4, Yosuke Togashi3, Takahiro Kamada3, Takuma Irie3, Genki Okumura3, Hidetoshi Kono3, Daisuke Ito3, Rika Fujii3, Sho Watanabe3, Atsuo Sai4, Shota Fukuoka3, Eri Sugiyama3, Go Watanabe3, Takuya Owari3, Hitomi Nishinakamura3, Daisuke Sugiyama5, Yuka Maeda3, Akihito Kawazoe6, Hiroki Yukami6, Keigo Chida6, Yuuki Ohara7, Tatsuya Yoshida8, Yuki Shinno8, Yuki Takeyasu8, Masayuki Shirasawa8, Kenta Nakama9, Keiju Aokage10, Jun Suzuki10, Genichiro Ishii7, Takeshi Kuwata7, Naoya Sakamoto7, Masahito Kawazu11, Toshihide Ueno11, Taisuke Mori12, Naoya Yamazaki9, Masahiro Tsuboi10, Yasushi Yatabe12, Takahiro Kinoshita13, Toshihiko Doi6, Kohei Shitara6, Hiroyuki Mano11, Hiroyoshi Nishikawa14.
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.Entities:
Keywords: MYC; PD-1; lactic acid; liver metastasis; regulatory T cell
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Year: 2022 PMID： 35090594 DOI： 10.1016/j.ccell.2022.01.001
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743