Sistema de Salut de Catalunya
Institut Català de la Salut
[Lin CP, Apriamashvili G, Ligtenberg MA, Vredevoogd DW] Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. [Levy PL] Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Tumor Immunology and Immunotherapy Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Alflen A] Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Hematology and Medical Oncology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany. Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg-University, Mainz, Germany
Vall d'Hebron Barcelona Hospital Campus
2024-04-16T06:58:24Z
2024-04-16T06:58:24Z
2024-04-08
Cèl·lules T; Mort cel·lular induïda per l'activació; Immunoteràpia contra el càncer
Células T; Muerte celular inducida por activación; Inmunoterapia contra el cáncer
T cells; Activation-induced cell death; Cancer immunotherapy
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.
This study has been funded by an ERC Advanced grant (grant agreement 101054465 [ReverT]) and a KWF grant (NKI 2015-7595) to D.S.P., and a DFG research fellowship (AL2295/1-1 and AL2295/1-2) to A.A. O.B.B. and M.A. acknowledge support of the X-Omics Initiative (Project 184.034.019), part of the NWO National Roadmap for Large-Scale Research Infrastructures. D.S.P. is funded by the Oncode Institute, which is partly financed by the Dutch Cancer Society KWF. Research at the Netherlands Cancer Institute is supported by institutional grants of the Dutch Cancer Society and the Dutch Ministry of Health, Welfare and Sport.
Article
Published version
English
Càncer - Tractament; Càncer - Aspectes genètics; Cèl·lules T; DISEASES::Neoplasms; Other subheadings::Other subheadings::Other subheadings::/genetics; ANATOMY::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes; ENFERMEDADES::neoplasias; Otros calificadores::Otros calificadores::Otros calificadores::/genética; ANATOMÍA::células::células sanguíneas::leucocitos::leucocitos mononucleares::linfocitos::linfocitos T
Cell Press
Cancer Cell;42(4)
https://doi.org/10.1016/j.ccell.2024.02.016
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
