对过继性 T 细胞疗法的临床反应与细胞产物的转录和表观遗传状态相关。因此，T细胞基因网络调节因子及其相应表型的发现有可能改善T细胞疗法。在这里，我们开发了表观遗传 CRISPR 筛选方法，系统地分析激活或抑制 120 个转录和表观遗传调节因子对人类 CD8 T 细胞状态的影响。我们发现 BATF3 过度表达促进了记忆 T 细胞的特定特征，并减弱了与细胞毒性、调节性 T 细胞功能和耗竭相关的基因程序。在慢性抗原刺激下，BATF3 过度表达抵消了 T 细胞耗竭的表型和表观遗传特征。此外，BATF3 增强了 CAR T 细胞在体外和体内肿瘤模型中的效力，并编程了与过继性 T 细胞治疗的积极临床反应相关的转录谱。最后，我们进行了 CRISPR 敲除筛选，确定了 BATF3 基因网络的辅因子和下游介质。© 2023。作者。

Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapies. Here we developed pooled, epigenetic CRISPR screening approaches to systematically profile the effects of activating or repressing 120 transcriptional and epigenetic regulators on human CD8+ T cell state. We found that BATF3 overexpression promoted specific features of memory T cells and attenuated gene programs associated with cytotoxicity, regulatory T cell function, and exhaustion. Upon chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. Moreover, BATF3 enhanced the potency of CAR T cells in both in vitro and in vivo tumor models and programmed a transcriptional profile that correlates with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens that defined cofactors and downstream mediators of the BATF3 gene network.© 2023. The Author(s).