Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation
Nicholas T. Crump, Andreas V. Hadjinicolaou, Xia Meng, John Walsby-Tickle, Uzi Gileadi, Ji‐Li Chen, Mashiko Setshedi, Lars Rønn Olsen, I‐Jun Lau, Laura Godfrey, Lynn Quek, Zhanru Yu, Erica Ballabio, Mike Bogetofte Barnkob, Giorgio Napolitani, Mariolina Salio, Hashem Koohy, Benedikt M. Kessler, Stephen Taylor, Paresh Vyas, James McCullagh, Thomas A. Milne, Vincenzo Cerundolo
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 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.