Chromatin accessibility governs the differential response of cancer and T-cells to arginine starvation (ChIP-seq)

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. Here, 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 CEBPbeta binding to a previously uncharacterized enhancer within ASS1. T-cells cannot induce ASS1, despite the presence of active ATF4 and CEBPbeta, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation which disrupts ATF4/CEBPbeta 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. ChIP-seq (33 samples)

消耗肿瘤微环境中精氨酸等关键营养物质，是癌细胞实现免疫逃逸的核心策略。诸多肿瘤会过度表达精氨酸酶，但目前尚不明确为何此类癌细胞而非T细胞能够耐受精氨酸匮乏环境。本研究证实，肿瘤细胞可通过上调精氨琥珀酸合成酶1（argininosuccinate synthetase 1，ASS1），以瓜氨酸为底物合成精氨酸。在精氨酸饥饿条件下，ATF4与CEBPβ结合至ASS1基因内一处此前未被表征的增强子区域，进而诱导ASS1的转录。尽管存在活性ATF4与CEBPβ，T细胞却无法诱导ASS1表达，因该基因处于转录抑制状态。精氨酸饥饿可引发全基因组染色质紧缩与抑制性组蛋白甲基化，这会破坏ATF4/CEBPβ的结合能力以及靶基因的转录过程。研究发现，在精氨酸匮乏的培养环境中，T细胞活化会受到显著损伤，其伴随的严重代谢紊乱与不完全染色质重塑以及关键基因的调控失常紧密相关。本研究结果揭示了一种由营养应激介导的T细胞行为模式，癌细胞可利用该模式完成病理性免疫逃逸。ChIP-seq（33例样本）