Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness.
Nat Metab
; 5(2): 314-330, 2023 02.
Article
em En
| MEDLINE
| ID: mdl-36717749
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acidose
/
Neoplasias
Limite:
Animals
Idioma:
En
Revista:
Nat Metab
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China