小柯机器人

美国杜克大学Charles A. Gersbach团队近期取得重要工作进展，他们通过正交CRISPR筛选鉴定出了人类CD8⁺ T细胞功能的转录和表观遗传调控因子。相关研究成果2023年11月9日在线发表于《自然—遗传学》杂志上。

据介绍，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学状态有关。因此，发现T细胞基因网络的调节因子及其相应的表型有可能改善T细胞治疗。

研究人员开发了汇总的表观遗传学CRISPR筛选方法，以系统地描述激活或抑制120个转录和表观遗传学调节因子对人类CD8⁺ T细胞状态的影响。研究人员发现BATF3过表达促进了记忆T细胞的特异性特征，并减弱了与细胞毒性、调节性T细胞功能和衰竭相关的基因程序。在慢性抗原刺激下，BATF3过表达对抗T细胞耗竭的表型和表观遗传学特征。

此外，BATF3在体外和体内肿瘤模型中增强了CAR T细胞的效力，并编程了与过继T细胞治疗的阳性临床反应相关的转录谱。最后，研究人员进行了CRISPR敲除筛选，确定了BATF3基因网络的辅助因子和下游介质。

附：英文原文

Title: Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens

Author: McCutcheon, Sean R., Swartz, Adam M., Brown, Michael C., Barrera, Alejandro, McRoberts Amador, Christian, Siklenka, Keith, Humayun, Lucas, ter Weele, Maria A., Isaacs, James M., Reddy, Timothy E., Allen, Andrew S., Nair, Smita K., Antonia, Scott J., Gersbach, Charles A.

Issue&Volume: 2023-11-09

Abstract: 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. CRISPR activation/interference screens identify transcriptional regulators of human CD8+ T cells, including BATF3. BATF3 overexpression counteracts T cell exhaustion and enhances cancer immunotherapy in in vivo models.

DOI: 10.1038/s41588-023-01554-0

Source: https://www.nature.com/articles/s41588-023-01554-0

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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