Multi-phenotype CRISPR-Cas9 Screen Identifies p38 Kinase as a Target for Adoptive Immunotherapies

Cancer Cell
Devikala GurusamyNicholas P Restifo

Abstract

T cells are central to all currently effective cancer immunotherapies, but the characteristics defining therapeutically effective anti-tumor T cells have not been comprehensively elucidated. Here, we delineate four phenotypic qualities of effective anti-tumor T cells: cell expansion, differentiation, oxidative stress, and genomic stress. Using a CRISPR-Cas9-based genetic screen of primary T cells we measured the multi-phenotypic impact of disrupting 25 T cell receptor-driven kinases. We identified p38 kinase as a central regulator of all four phenotypes and uncovered transcriptional and antioxidant pathways regulated by p38 in T cells. Pharmacological inhibition of p38 improved the efficacy of mouse anti-tumor T cells and enhanced the functionalities of human tumor-reactive and gene-engineered T cells, paving the way for clinically relevant interventions.

References

Jan 1, 1993·International Immunology·E EylarC M Mercado
Apr 16, 1998·The Journal of Biological Chemistry·E P RogakouW M Bonner
Aug 20, 2003·The Journal of Experimental Medicine·Willem W OverwijkNicholas P Restifo
Mar 10, 2005·The Journal of Biological Chemistry·Yvonne KumaAna Cuenda
Mar 22, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yangbing ZhaoRichard A Morgan
May 8, 2007·Biochimica Et Biophysica Acta·Ana Cuenda, Simon Rousseau
Jun 23, 2009·Nature·Koichi ArakiRafi Ahmed
Apr 19, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Steven A RosenbergMark E Dudley
Jul 9, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Christopher A KlebanoffNicholas P Restifo
Sep 20, 2011·Nature Medicine·Luca GattinoniNicholas P Restifo
Dec 31, 2011·Immunity·Gerritje J W van der WindtErika L Pearce
Sep 4, 2012·Antioxidants & Redox Signaling·Pravin KesarwaniShikhar Mehrotra
Jan 12, 2013·European Journal of Immunology·Julia RolfDoreen A Cantrell
May 22, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Michal J BesserJacob Schachter
Dec 18, 2013·Immunological Reviews·Christian S Hinrichs, Steven A Rosenberg
Dec 18, 2013·Immunological Reviews·Joseph G CromptonNicholas P Restifo
Mar 7, 2014·Journal of Immunotherapy·Shannon F RosatiRichard A Morgan
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
Apr 4, 2015·Science·Steven A Rosenberg, Nicholas P Restifo
Sep 22, 2015·The Journal of Clinical Investigation·Cyrille J CohenPaul F Robbins
Dec 18, 2015·Cell Metabolism·Madhusudhanan SukumarNicholas P Restifo
Jan 19, 2016·Nature Biotechnology·John G DoenchDavid E Root
May 25, 2016·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Stephanie L GoffSteven A Rosenberg
Feb 16, 2017·Nature Immunology·Eric TranSteven A Rosenberg
Aug 8, 2017·Nature·Shashank J PatelNicholas P Restifo
Nov 24, 2017·Science Translational Medicine·Yinmeng YangTerry J Fry
Mar 17, 2018·Nature Reviews. Drug Discovery·Fleur M Ferguson, Nathanael S Gray
May 26, 2018·Nature Reviews. Drug Discovery·Jun TangAiman Shalabi
Oct 9, 2019·Nature Medicine·Tori N YamamotoNicholas P Restifo

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Citations

Sep 23, 2020·Journal of Cellular Physiology·Baohong Zhang
Sep 15, 2020·Current Opinion in Hematology·Ofrat Beyar-Katz, Saar Gill
Jan 29, 2021·Nature Reviews. Molecular Cell Biology·Begoña Canovas, Angel R Nebreda
Feb 13, 2021·Annals of Surgical Oncology·Chigozirim N EkekeRajeev Dhupar
Apr 3, 2021·Cancer Immunology, Immunotherapy : CII·Marco StringhiniDario Neri
Mar 31, 2021·British Journal of Cancer·Matteo MorottiAhmed A Ahmed
Apr 6, 2021·Frontiers in Immunology·Guillermo O Rangel RiveraChrystal M Paulos
Apr 29, 2021·EBioMedicine·Ella S AtsavapraneeMichael J Mitchell
May 12, 2021·Nature Reviews. Drug Discovery·Andrew J HouYvonne Y Chen
Apr 7, 2021·Cold Spring Harbor Perspectives in Biology·Jana L RaynorHongbo Chi
Jun 10, 2020·Cancer Cell·Jack D ChanPhillip K Darcy
May 28, 2021·Biologics : Targets & Therapy·Maya GloverJohn Maher
May 29, 2021·EBioMedicine·Jie ZhangHongyan Guo
May 29, 2021·RSC Medicinal Chemistry·Lewis L BrayshawChristopher Herring
Jun 15, 2021·International Immunopharmacology·Siyin ChenAishun Jin
Jul 10, 2021·Frontiers in Cell and Developmental Biology·Fabio Grassi, Benedetta De Ponte Conti
Jul 10, 2021·Biotechnology and Bioengineering·Muhammad Sadeqi NezhadNader Bagheri
Aug 11, 2021·Annals of Oncology : Official Journal of the European Society for Medical Oncology·D MeyranP J Neeson
Aug 27, 2021·Frontiers in Immunology·Valérie JanelleJean-Sébastien Delisle
Dec 4, 2021·Cell·Charly R GoodCarl H June
Dec 29, 2021·Immunological Medicine·Rafael Cardoso Maciel Costa SilvaBruno Ricardo Barreto Pires

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