Cell Reports (Mar 2023)

Accumulation of branched-chain amino acids reprograms glucose metabolism in CD8+ T cells with enhanced effector function and anti-tumor response

  • Cheng-cheng Yao,
  • Rui-ming Sun,
  • Yi Yang,
  • Hai-yan Zhou,
  • Zhou-wenli Meng,
  • Rui Chi,
  • Li-liang Xia,
  • Ping Ji,
  • Ying-ying Chen,
  • Guo-qing Zhang,
  • Hai-peng Sun,
  • Shun Lu,
  • Chen Yang,
  • Ying Wang

Journal volume & issue
Vol. 42, no. 3
p. 112186

Abstract

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Summary: Branched-chain amino acids (BCAAs) provide nutrient signals for cell survival and growth. How BCAAs affect CD8+ T cell functions remains unexplored. Herein, we report that accumulation of BCAAs in CD8+ T cells due to the impairment of BCAA degradation in 2C-type serine/threonine protein phosphatase (PP2Cm)-deficient mice leads to hyper-activity of CD8+ T cells and enhanced anti-tumor immunity. CD8+ T cells from PP2Cm−/− mice upregulate glucose transporter Glut1 expression in a FoxO1-dependent manner with more glucose uptake, as well as increased glycolysis and oxidative phosphorylation. Moreover, BCAA supplementation recapitulates CD8+ T cell hyper-functions and synergizes with anti-PD-1, in line with a better prognosis in NSCLC patients containing high BCAAs when receiving anti-PD-1 therapy. Our finding thus reveals that accumulation of BCAAs promotes effector function and anti-tumor immunity of CD8+ T cells through reprogramming glucose metabolism, making BCAAs alternative supplementary components to increase the clinical efficacy of anti-PD-1 immunotherapy against tumors.

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