Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation

Journal article

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 CEBPβ binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPβ, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPβ 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.

Authors: Crump, NT; Hadjinicolaou, AV; Xia, M; Walsby-Tickle, J; Gileadi, U

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell Reports
• Volume: 35
• Issue: 6
• Article number: 109101
• Publication date: 2021-05-11
• Acceptance date: 2021-04-16
• DOI: 10.1016/j.celrep.2021.109101
• ISSN: 2211-1247
• Language: English
• Keywords: FFR; nutritional stress; T cell chromatin; ASS1; metabolic regulation; ATF4; cancer metabolism; arginine; H3K27me3; immunometabolism; immunosuppression