Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation.
Cell Rep
; 35(6): 109101, 2021 05 11.
Article
en En
| MEDLINE
| ID: mdl-33979616
ABSTRACT
Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it is unclear how these cancers, but not T cells, tolerate arginine depletion. In this study, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPß binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPß, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPß binding and target gene transcription. We find that T cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Arginina
/
Cromatina
/
Linfocitos T
/
Evasión Inmune
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Neoplasias
Límite:
Animals
/
Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article