Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Tumor Immunology and Immunotherapy Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain.
Cancer Cell. 2024 Apr 8;42(4):623-645.e10. doi: 10.1016/j.ccell.2024.02.016. Epub 2024 Mar 14.
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.
限制 T 细胞抗肿瘤活性的基因可能成为治疗靶点。目前尚未系统研究是否存在独特或广泛影响 T 细胞适应性的调节剂。我们在原代 CD8 T 细胞中进行了全基因组规模的 CRISPR-Cas9 敲除筛选，以发现三种刺激模式（1）强烈，引发激活诱导的细胞死亡（AICD）；（2）急性，引发扩增；（3）慢性，导致功能障碍）对适应性有负面影响的基因。除了已建立的调节剂外，我们还发现了在不同刺激下特异性或共同控制 T 细胞适应性的基因。Dap5 缺失在所有三种筛选中排名都很高，它在提高翻译的同时增强了肿瘤杀伤能力。在急性和强烈刺激后，丧失 Icam1 介导的同种型 T 细胞聚集作用会增强细胞扩增和效应功能。最后，Ctbp1 失活仅在慢性刺激时诱导功能 T 细胞的持久性。我们的结果根据它们对限制 T 细胞抗肿瘤活性的特性的独特或共同贡献，对适应性调节剂进行了功能注释。
