Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness
Lin, Chun Pu; Levy, Pierre L.; Alflen, Astrid; Apriamashvili, Georgi; Ligtenberg, Maarten A.; Vredevoogd, David W.; Bleijerveld, Onno B.; Alkan, Ferhat; Malka, Yuval; Hoekman, Liesbeth; Markovits, Ettai; George, Austin; Traets, Joleen J.H.; Krijgsman, Oscar; van Vliet, Alex; Poźniak, Joanna; Pulido-Vicuña, Carlos Ariel; de Bruijn, Beaunelle; van Hal-van Veen, Susan E.; Boshuizen, Julia; van der Helm, Pim W.; Díaz-Gómez, Judit; Warda, Hamdy; Behrens, Leonie M.; Mardesic, Paula; Dehni, Bilal; Visser, Nils L.; Marine, Jean Christophe; Markel, Gal; Faller, William J.; Altelaar, Maarten; Agami, Reuven; Besser, Michal J.; Peeper, Daniel S.
(2024) Cancer Cell, volume 42, issue 4, pp. 623 - 645
(Article)
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
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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.
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Keywords: activation-induced cell death, cancer immunotherapy, CRISPR-Cas9 screen, Ctbp1, Dap5, dysfunction, effector function, exhaustion, Icam1, T cells, Oncology, Cancer Research
ISSN: 1535-6108
Publisher: Cell Press
Note: Publisher Copyright: © 2024 The Authors
(Peer reviewed)