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

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

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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.

TidsskriftCell Reports
Udgave nummer6
StatusUdgivet - 11. maj 2021
Udgivet eksterntJa

Bibliografisk note

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.


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