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

doi:10.1016/j.celrep.2023.112186

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

Cell Rep. 2023 Mar 28;42(3):112186. doi: 10.1016/j.celrep.2023.112186. Epub 2023 Mar 6.

Authors

Cheng-Cheng Yao¹, Rui-Ming Sun¹, Yi Yang², Hai-Yan Zhou³, Zhou-Wenli Meng², Rui Chi⁴, Li-Liang Xia², Ping Ji¹, Ying-Ying Chen¹, Guo-Qing Zhang⁵, Hai-Peng Sun⁶, Shun Lu⁷, Chen Yang⁸, Ying Wang⁹

Affiliations

¹ Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
² Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
³ CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences (CAS), Shanghai 200032, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine; Shanghai 200025, China.
⁵ Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Science, Shanghai 200031, China.
⁶ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine; Shanghai 200025, China; NHC Key Laboratory of Hormones and Development, Center for Cardiovascular Diseases, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China. Electronic address: sun.haipeng@tmu.edu.cn.
⁷ Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: shunlu@sjtu.edu.cn.
⁸ CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences (CAS), Shanghai 200032, China. Electronic address: cyang@cemps.ac.cn.
⁹ Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. Electronic address: ywangssmu@shsmu.edu.cn.

PMID: 36870057
DOI: 10.1016/j.celrep.2023.112186

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.

Keywords: CD8(+) T cells; CP: Immunology; anti-tumor immunity; branched-chain amino acid accumulation; effector function; glucose metabolism; synergy with anti-PD-1 treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids, Branched-Chain* / metabolism
Animals
CD8-Positive T-Lymphocytes* / metabolism
Glucose
Mice

Substances

Amino Acids, Branched-Chain
Glucose