| Autor: |
Liu, Ying, Wang, Feng, Peng, Dongxue, Zhang, Dan, Liu, Luping, Wei, Jun, Yuan, Jian, Zhao, Luyao, Jiang, Huimin, Zhang, Tingting, Li, Yunxuan, Zhao, Chenxi, He, Shuhua, Wu, Jie, Yan, Yechao, Zhang, Peitao, Guo, Chunyi, Zhang, Jiaming, Li, Xia, Gao, Huan |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 8/28/2024, Vol. 16 Issue 762, p1-18, 18p |
| Abstrakt: |
CD8+ T cell activation leads to the rapid proliferation and differentiation of effector T cells (Teffs), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8+ Teffs, the mechanisms that regulate CD8+ T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8+ T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8+ T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8+ T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8+ T cells by directly binding to GLUT10's intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8+ T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti–programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8+ T cells and identify that TME accumulated lactic acid inhibits CD8+ T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8+ T cell–mediated antitumor effects. Editor's summary: CD8+ T cells are a critical part of antitumor immunity and depend on metabolites including glucose to maintain their function. Here, Liu et al. have evaluated targeting glucose transport 10 (GLUT10) as a way to increase CD8+ T cell function by disrupting the competitive binding of lactic acid that increased glucose uptake, thereby increasing proliferation and antitumor capacity. Authors developed a mimic peptide, PG10.3, to treat mouse models alone or in combination with anti–programmed cell death 1 to improve antitumor effects. This represents a new potential therapeutic option to improve outcomes for patients undergoing immunotherapy that will require further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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