Liu Guolong, Tian Xiaoling, Wang Qiudao, Xu Saijuan, Jiang Yanhong, Gao Ying, Wu Yuxuan
Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
YolTech Therapeutics, Shanghai 201199, China.
Sci Adv. 2025 Aug 15;11(33):eadx9221. doi: 10.1126/sciadv.adx9221.
CD8 T play essential roles in antitumor immune responses. However, immunotherapy has limited clinical efficacy in many solid tumors. Here, we performed an epigenetic-wide CRISPR-Cas9 screen in CD8 T cells directly under cancer immunotherapy setting and found that is a transcriptional repressor implicated in nociceptive neuron development but uncharacterized within immunological contexts. deletion markedly enhanced in vivo tumor clearance of mouse CD8 T cells and promoted activation, effector differentiation marker expression, and cytokine secretion in both murine and human CD8 T cells in vitro. Mechanistically, deficiency augmented effector transcriptional programs while inhibiting exhaustion of CGRP-RAMP1 neuroimmune axis facilitation. Additionally, ablation remodeled the chromatin accessibility landscape, with H3K9me3 deposition at loci regulating T cell differentiation ( and ) and exhaustion ( and ). These results together reveal a negative regulatory mechanism for CD8 T cells and advance our understanding of cancer immunotherapy by linking neurobiological signaling to immune regulation.
CD8 T细胞在抗肿瘤免疫反应中发挥着重要作用。然而，免疫疗法在许多实体瘤中的临床疗效有限。在此，我们在癌症免疫治疗环境下直接对CD8 T细胞进行了全表观基因组CRISPR-Cas9筛选，发现[此处原文缺失具体基因名称]是一种转录抑制因子，与伤害性神经元发育有关，但在免疫背景下尚未得到充分研究。[此处原文缺失具体基因名称]的缺失显著增强了小鼠CD8 T细胞在体内的肿瘤清除能力，并在体外促进了小鼠和人类CD8 T细胞的激活、效应分化标志物表达和细胞因子分泌。从机制上讲，[此处原文缺失具体基因名称]缺陷增强了效应转录程序，同时抑制了降钙素基因相关肽-受体活性修饰蛋白1（CGRP-RAMP1）神经免疫轴促进的耗竭。此外，[此处原文缺失具体基因名称]的缺失重塑了染色质可及性景观，在调节T细胞分化（[此处原文缺失具体基因名称]和[此处原文缺失具体基因名称]）和耗竭（[此处原文缺失具体基因名称]和[此处原文缺失具体基因名称]）的基因座上有H3K9me3沉积。这些结果共同揭示了CD8 T细胞的一种负调控机制，并通过将神经生物学信号与免疫调节联系起来，推进了我们对癌症免疫治疗的理解。
