Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation.
Cell Rep
; 35(6): 109101, 2021 05 11.
Article
in 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Arginine
/
Chromatin
/
T-Lymphocytes
/
Immune Evasion
/
Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell Rep
Year:
2021
Type:
Article
Affiliation country:
United kingdom