Chromatin accessibility governs the differential response of cancer and T-cells to arginine starvation (ATAC-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. Overall design: ATAC-seq (33 samples)

剥夺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。诸多肿瘤会过表达精氨酸酶，但目前尚不清楚为何此类癌细胞可耐受精氨酸匮乏，而T细胞却无法耐受。本研究发现，癌细胞可通过上调精氨酸琥珀酸合成酶1（argininosuccinate synthetase 1, ASS1），以瓜氨酸为原料合成精氨酸。在精氨酸饥饿状态下，ATF4与CEBPβ结合至ASS1基因内一处此前未被鉴定的增强子区域，从而诱导ASS1的转录。尽管T细胞内存在活性ATF4与CEBPβ，但由于ASS1基因处于抑制状态，其无法诱导ASS1的表达。精氨酸匮乏会引发全基因组染色质浓缩以及抑制性组蛋白甲基化修饰，进而破坏ATF4/CEBPβ的结合能力与靶基因的转录过程。研究发现，在精氨酸匮乏的环境中，T细胞的活化会受到损伤，这种损伤与染色质重塑不完全以及关键基因的表达失调引发的严重代谢紊乱密切相关。本研究结果揭示了一种由营养应激介导的T细胞行为，该行为被癌细胞利用以实现病理性免疫逃逸。实验整体设计：ATAC-seq（共33个样本）