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

Autor:	Lin CP; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Levy PL; 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., Alflen A; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Department of Hematology and Medical Oncology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg-University, 55131 Mainz, Germany., Apriamashvili G; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Ligtenberg MA; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Vredevoogd DW; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Bleijerveld OB; Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Alkan F; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Malka Y; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Hoekman L; Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Markovits E; Ella Lemelbaum Institute for Immuno-oncology and Melanoma, Sheba Medical Center, Ramat Gan 52612, Israel; Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel., George A; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Traets JJH; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Krijgsman O; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., van Vliet A; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Poźniak J; Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, 3000 Leuven, Belgium; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, 3000 Leuven, Belgium., Pulido-Vicuña CA; Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, 3000 Leuven, Belgium; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, 3000 Leuven, Belgium., de Bruijn B; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., van Hal-van Veen SE; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Boshuizen J; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., van der Helm PW; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Díaz-Gómez J; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Warda H; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Behrens LM; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Mardesic P; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Dehni B; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Visser NL; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Marine JC; Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, 3000 Leuven, Belgium; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, 3000 Leuven, Belgium., Markel G; Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel; Davidoff Cancer Center and Samueli Integrative Cancer Pioneering Institute, Rabin Medical Center, Petach Tikva 4941492, Israel., Faller WJ; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Altelaar M; Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Biomolecular Mass Spectrometry and Proteomics, Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands., Agami R; Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Besser MJ; Ella Lemelbaum Institute for Immuno-oncology and Melanoma, Sheba Medical Center, Ramat Gan 52612, Israel; Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel; Davidoff Cancer Center and Samueli Integrative Cancer Pioneering Institute, Rabin Medical Center, Petach Tikva 4941492, Israel; Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel., Peeper DS; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Department of Pathology, VU University Amsterdam, 1081 HV Amsterdam, the Netherlands. Electronic address: d.peeper@nki.nl.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2024 Apr 08; Vol. 42 (4), pp. 623-645.e10. Date of Electronic Publication: 2024 Mar 14.
DOI:	10.1016/j.ccell.2024.02.016
Abstrakt:	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. Competing Interests: Declaration of interests C.L., P.L., A.A., G.A., M.A.L., D.W.V., and D.S.P. are named as inventors on a patent filed by the Netherlands Cancer Institute and Oncode on the findings described in this manuscript. D.S.P. and M.A.L. are co-founders, shareholders, and advisors of Immagene. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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