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

Crump, Nicholas T.; Hadjinicolaou, Andreas V.; Xia, Meng; Walsby-Tickle, John; Gileadi, Uzi; Chen, Ji-Li; Setshedi, Mashiko; Olsen, Lars R.; Lau, I-Jun; Godfrey, Laura; Quek, Lynn; Yu, Zhanru; Ballabio, Erica; Barnkob, Mike B.; Napolitani, Giorgio; Salio, Mariolina; Koohy, Hashem; Kessler, Benedikt M.; Taylor, Stephen; Vyas, Paresh; McCullagh, James S.O.; Milne, Thomas A.; Cerundolo, Vincenzo

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.