2. Academic Validation
  3. Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness

Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness

  • Nat Metab. 2023 Jan 30. doi: 10.1038/s42255-022-00730-6.
Hongcheng Cheng # 1 2,  Yajing Qiu # 1 2,  Yue Xu # 1 2,  Li Chen # 3,  Kaili Ma 1 2,  Mengyuan Tao 1 2 4,  Luke Frankiw 5,  Hongli Yin 1 2,  Ermei Xie 1 2 6,  Xiaoli Pan 1 2,  Jing Du 1 2,  Zhe Wang 1 2,  Wenjie Zhu 1 2,  Lu Chen 7,  Lianjun Zhang 8 9 10,  Guideng Li 11 12
Affiliations

Affiliations

  • 1 Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 Suzhou Institute of Systems Medicine, Suzhou, China.
  • 3 Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 4 School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
  • 5 Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
  • 6 Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China.
  • 7 Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
  • 8 Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 9 Suzhou Institute of Systems Medicine, Suzhou, China. [email protected].
  • 10 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China. [email protected].
  • 11 Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
  • 12 Suzhou Institute of Systems Medicine, Suzhou, China. [email protected].
  • # Contributed equally.
PMID: 36717749 DOI: 10.1038/s42255-022-00730-6
Abstract

The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an acidic environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms T cell intracellular metabolism and mitochondrial fitness and preserves T cell stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake and metabolism via downregulation of SLC7A5, therefore altering H3K27me3 deposition at the promoters of key T cell stemness genes. These changes promote the maintenance of a 'stem-like memory' state and improve long-term in vivo persistence and anti-tumor efficacy in mice. Our findings not only reveal an unexpected capacity of extracellular acidosis to maintain the stem-like properties of T cells, but also advance our understanding of how methionine metabolism affects T cell stemness.

Figures
Products