MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Cell Rep. 2021 May 11;35(6):109101. doi: 10.1016/j.celrep.2021.109101.
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.
消耗精氨酸等重要营养物质的微环境是癌细胞免疫逃逸的关键策略。许多肿瘤过度表达精氨酸酶，但尚不清楚这些癌症（而不是 T 细胞）如何耐受精氨酸耗竭。在这项研究中，我们表明肿瘤细胞通过上调精氨酰琥珀酸合成酶 1（ASS1）从瓜氨酸合成精氨酸。在精氨酸饥饿下，ASS1 转录由 ATF4 和 CEBPβ 与 ASS1 内的增强子结合诱导。尽管存在活性 ATF4 和 CEBPβ，T 细胞不能诱导 ASS1，因为该基因被抑制。精氨酸饥饿会导致全局染色质紧缩和抑制性组蛋白甲基化，从而破坏 ATF4/CEBPβ 结合和靶基因转录。我们发现，在缺乏精氨酸的条件下，T 细胞的激活受到损害，与不完全染色质重塑和关键基因的失调相关的显著代谢扰动。我们的结果强调了一种由营养压力介导的 T 细胞行为，被癌细胞利用来实现病理性免疫逃逸。
