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

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 trans location 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.

Automated summary

In highly glycolytic tumors, regulatory T (Treg) cells have higher PD-1 expression compared to effector T cells. Under low-glucose conditions, Treg cells actively absorb lactic acid through monocarboxylate transporter 1 (MCT1), promoting the expression of PD-1, while PD-1 expression by effector T cells is dampened. PD-1 blockade invigorates PD-1-expressing Treg cells, resulting in treatment failure.