TY - JOUR
T1 - Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation
AU - Crump, Nicholas T.
AU - Hadjinicolaou, Andreas, V
AU - Xia, Meng
AU - Walsby-Tickle, John
AU - Gileadi, Uzi
AU - Chen, Ji-Li
AU - Setshedi, Mashiko
AU - Olsen, Lars R.
AU - Lau, I-Jun
AU - Godfrey, Laura
AU - Quek, Lynn
AU - Yu, Zhanru
AU - Ballabio, Erica
AU - Barnkob, Mike B.
AU - Napolitani, Giorgio
AU - Salio, Mariolina
AU - Koohy, Hashem
AU - Kessler, Benedikt M.
AU - Taylor, Stephen
AU - Vyas, Paresh
AU - McCullagh, James S. O.
AU - Milne, Thomas A.
AU - Cerundolo, Vincenzo
N1 - Funding Information:
We thank the late V.C. as an inspirational colleague, mentor, and pioneer in the field, who passed away during the completion of this manuscript. We gratefully acknowledge Christian Frezza and Magdalena Winiarska for their helpful comments on the manuscript. This work was supported by the UK Medical Research Council (MRC Human Immunology Unit grant MC_UU_12010/3 and Molecular Haematology Unit grants MC_UU_12009/6 and MC_UU_00016/6 ), the Oxford Biomedical Research Centre , and by Cancer Research UK (Programme Grant C399/A2291 to V.C.). A.V.H. was supported by a Wellcome Trust Clinical Research Fellowship and an A.G. Leventis Foundation Scholarship .
Funding Information:
We thank the late V.C. as an inspirational colleague, mentor, and pioneer in the field, who passed away during the completion of this manuscript. We gratefully acknowledge Christian Frezza and Magdalena Winiarska for their helpful comments on the manuscript. This work was supported by the UK Medical Research Council (MRC Human Immunology Unit grant MC_UU_12010/3 and Molecular Haematology Unit grants MC_UU_12009/6 and MC_UU_00016/6), the Oxford Biomedical Research Centre, and by Cancer Research UK (Programme Grant C399/A2291 to V.C.). A.V.H. was supported by a Wellcome Trust Clinical Research Fellowship and an A.G. Leventis Foundation Scholarship. N.T.C. A.V.H. M.X. J.W.-T. U.G. J.-L.C. M. Setshedi, I.-J.L. L.G. Z.Y. and E.B. conducted the experiments; N.T.C. A.V.H. M.X. T.A.M. and V.C. designed the experiments; N.T.C. A.V.H. M.X. J.W.-T. M.B.B. L.R.O. and H.K. analyzed the data; L.Q. M. Salio, G.N. P.V. and J.S.O.M. provided expertise and feedback; B.M.K. S.T. P.V. J.S.O.M. T.A.M. and V.C. provided supervision; N.T.C. A.V.H. T.A.M. and V.C. wrote the paper; all authors reviewed the paper. T.A.M. and P.V. are founder shareholders of OxStem Oncology (OSO), a subsidiary company of OxStem Ltd. M. Salio consults for Nucleome Therapeutics Ltd. The remaining authors declare no competing interests.
Publisher Copyright:
© 2021 The Author(s)
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5/11
Y1 - 2021/5/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105842711&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2021.109101
DO - 10.1016/j.celrep.2021.109101
M3 - Article
C2 - 33979616
SN - 2211-1247
VL - 35
SP - 109101
JO - Cell Reports
JF - Cell Reports
IS - 6
M1 - 109101
ER -
