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, Haiyan Zhou, Zhouwenli Meng, Rui Chi, Liliang Xia, Ping Ji, Yingying Chen, Guoqing Zhang, Haipeng Sun, Shun Lü, Chen Yang, Ying Wang
Abstract
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.