美国国立卫生研究院Nicholas P. Restifo、Shashank J. Patel和Devikala Gurusamy研究团队利用多表型CRISPR-Cas9筛选，揭示了p38激酶为过继免疫疗法的靶点。相关论文于2020年6月8日发表在《癌细胞》杂志上。

在该研究中，研究人员揭示了有效抗肿瘤T细胞的四种表型特征：细胞扩增、分化、氧化应激和基因组应激。使用基于CRISPR-Cas9的原代T细胞遗传筛选系统，研究人员检测了破坏25 种T细胞受体诱导性激酶对多表型的影响。

研究人员发现p38激酶是所有四种表型的核心调控因子，并且未发现p38在T细胞中调控转录和抗氧化的途径。对p38进行药物抑制可提高小鼠抗肿瘤T细胞的功效，并增强人类肿瘤反应性和基因工程T细胞的功能。该研究为临床相关干预措施铺平了道路。

据悉，T细胞是目前所有有效癌症免疫疗法的核心功能细胞，但尚无研究全面阐明在治疗上有抗肿瘤效果T细胞的特征。

附：英文原文

Title: Multi-phenotype CRISPR-Cas9 Screen Identifies p38 Kinase as a Target for Adoptive Immunotherapies

Author: Devikala Gurusamy, Amanda N. Henning, Tori N. Yamamoto, Zhiya Yu, Nikolaos Zacharakis, Sri Krishna, Rigel J. Kishton, Suman K. Vodnala, Arash Eidizadeh, Li Jia, Christine M. Kariya, Mary A. Black, Robert Eil, Douglas C. Palmer, Jenny H. Pan, Madhusudhanan Sukumar, Shashank J. Patel, Nicholas P. Restifo

Issue&Volume: 2020/06/08

Abstract: T cells are central to all currently effective cancer immunotherapies, but the characteristicsdefining therapeutically effective anti-tumor T cells have not been comprehensivelyelucidated. Here, we delineate four phenotypic qualities of effective anti-tumor T cells:cell expansion, differentiation, oxidative stress, and genomic stress. Using a CRISPR-Cas9-basedgenetic screen of primary T cells we measured the multi-phenotypic impact of disrupting25 T cell receptor-driven kinases. We identified p38 kinase as a central regulatorof all four phenotypes and uncovered transcriptional and antioxidant pathways regulatedby p38 in T cells. Pharmacological inhibition of p38 improved the efficacy of mouseanti-tumor T cells and enhanced the functionalities of human tumor-reactive and gene-engineeredT cells, paving the way for clinically relevant interventions.

DOI: 10.1016/j.ccell.2020.05.004

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30254-3