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

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

Cancer Cell

Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo 104-0045/Chiba 277-8577, Japan; Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address:

Published: February 2022

AI Article Synopsis

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.

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Source
http://dx.doi.org/10.1016/j.ccell.2022.01.001DOI Listing

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