荷兰癌症研究所Daniel S. Peeper团队发现，多模式刺激筛选揭示限制T细胞适应性的独特基因和共有基因。相关论文于2024年3月14日在线发表在《癌细胞》杂志上。

研究人员在原代CD8 T细胞中进行了基因组规模的CRISPR-Cas9基因敲除筛选，发现了在三种刺激模式下对T细胞活力产生负面影响的基因：（1）强烈刺激，引发活化诱导细胞死亡（AICD）；（2）急性刺激，引发扩增；（3）慢性刺激，导致功能障碍。除了已有的调节因子外，研究人员还发现了在不同刺激下特异或共同控制T细胞适应性的基因。

在所有三个筛选中，Dap5的消减排名都很高，它在增强肿瘤杀伤力的同时也增加了翻译。Icam1介导的同型T细胞集群的缺失会在急性和强烈刺激后，扩大细胞扩增和效应功能。最后，Ctbp1失活只能在慢性刺激下诱导功能性T细胞持续存在。这些研究结果根据适应性调节因子，对限制T细胞抗肿瘤活性的特征的独特或共同贡献，对这些因子进行了功能性注释。

据了解，限制T细胞抗肿瘤活性的基因可作为治疗目标。目前还没有系统地研究过是否有调节因子，独特或广泛地影响T细胞的适应性。

附：英文原文

Title: Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

Author: Chun-Pu Lin, Pierre L. Levy, Astrid Alflen, Georgi Apriamashvili, Maarten A. Ligtenberg, David W. Vredevoogd, Onno B. Bleijerveld, Ferhat Alkan, Yuval Malka, Liesbeth Hoekman, Ettai Markovits, Austin George, Joleen J.H. Traets, Oscar Krijgsman, Alex van Vliet, Joanna Poniak, Carlos Ariel Pulido-Vicua, Beaunelle de Bruijn, Susan E. van Hal-van Veen, Julia Boshuizen, Pim W. van der Helm, Judit Díaz-Gómez, Hamdy Warda, Leonie M. Behrens, Paula Mardesic, Bilal Dehni, Nils L. Visser, Jean-Christophe Marine, Gal Markel, William J. Faller, Maarten Altelaar, Reuven Agami, Michal J. Besser, Daniel S. Peeper

Issue&Volume: 2024-03-14

Abstract: Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity.

DOI: 10.1016/j.ccell.2024.02.016

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00060-6