为了确定限制T细胞功能的基因，研究人员在人类嵌合抗原受体（CAR）T细胞中进行了全基因组CRISPR敲除筛选。排名靠前的是MED12和CCNC，它们是中介体激酶模块的组成部分。靶向MED12的缺失增强了抗肿瘤活性，并维持了CAR和T细胞受体工程T细胞的效应表型，而CDK8/19激酶活性的抑制增加了非工程T细胞的扩增。
MED12缺陷的T细胞在转录活跃的增强子上表现出核心中介体染色质占有率增加，最明显的是STAT和AP-1转录因子，以及IL2RA表达和白细胞介素-2敏感性增加。这些结果揭示出中介体在T细胞效应子编程中的作用，并确定激酶模块是提高抗肿瘤T细胞反应效力的靶标。
据悉，T细胞是免疫系统中负责控制和压制癌症的主要部门。
附：英文原文
Title: Enhanced T cell effector activity by targeting the Mediator kinase module
Author: Katherine A. Freitas, Julia A. Belk, Elena Sotillo, Patrick J. Quinn, Maria C. Ramello, Meena Malipatlolla, Bence Daniel, Katalin Sandor, Dorota Klysz, Jeremy Bjelajac, Peng Xu, Kylie A. Burdsall, Victor Tieu, Vandon T. Duong, Micah G. Donovan, Evan W. Weber, Howard Y. Chang, Robbie G. Majzner, Joaquin M. Espinosa, Ansuman T. Satpathy, Crystal L. Mackall
Issue&Volume: 2022-11-11
Abstract: T cells are the major arm of the immune system responsible for controlling and regressing cancers. To identify genes limiting T cell function, we conducted genome-wide CRISPR knockout screens in human chimeric antigen receptor (CAR) T cells. Top hits were MED12 and CCNC, components of the Mediator kinase module. Targeted MED12 deletion enhanced antitumor activity and sustained the effector phenotype in CAR- and T cell receptor–engineered T cells, and inhibition of CDK8/19 kinase activity increased expansion of nonengineered T cells. MED12-deficient T cells manifested increased core Meditator chromatin occupancy at transcriptionally active enhancers—most notably for STAT and AP-1 transcription factors—and increased IL2RA expression and interleukin-2 sensitivity. These results implicate Mediator in T cell effector programming and identify the kinase module as a target for enhancing potency of antitumor T cell responses.
DOI: abn5647
Source: https://www.science.org/doi/10.1126/science.abn5647