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Activation and antitumor immunity of CD8 + T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid.

Ying LiuFeng WangDongxue PengDan ZhangLuping LiuJun WeiJian YuanLuyao ZhaoHuimin JiangTingting ZhangYun-Xuan LiChenxi ZhaoShuhua HeJie WuYechao YanPeitao ZhangChunyi GuoJiaming ZhangXia LiHuan GaoKe Li
Published in: Science translational medicine (2024)
CD8 + T cell activation leads to the rapid proliferation and differentiation of effector T cells (T effs ), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8 + T effs , 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.
Keyphrases
  • lactic acid
  • blood glucose
  • type diabetes
  • dendritic cells
  • regulatory t cells
  • transcription factor
  • ms ms
  • artificial intelligence
  • weight loss
  • climate change
  • human health
  • functional connectivity