@article{f11bd3ef21f2466285989787b083c8e5,
title = "Multi-phenotype CRISPR-Cas9 Screen Identifies p38 Kinase as a Target for Adoptive Immunotherapies",
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.",
keywords = "CD19 CAR T cell, CRISPR-Cas9 screen, DNA damage, NY-ESO-1, ROS, adoptive transfer immunotherapy, differentiation, multi-phenotype, neoantigen TIL, p38",
author = "Devikala Gurusamy and Henning, {Amanda N.} and Yamamoto, {Tori N.} and Zhiya Yu and Nikolaos Zacharakis and Sri Krishna and Kishton, {Rigel J.} and Vodnala, {Suman K.} and Arash Eidizadeh and Li Jia and Kariya, {Christine M.} and Black, {Mary A.} and Robert Eil and Palmer, {Douglas C.} and Pan, {Jenny H.} and Madhusudhanan Sukumar and Patel, {Shashank J.} and Restifo, {Nicholas P.}",
note = "Funding Information: The research was supported by the Intramural Research Program of the NCI , and by the Cancer Moonshot program for the Center for Cell-based Therapy at the NCI, NIH. The work was also supported by the Milken Family Foundation . The work presented here was entirely performed at the NIH. We thank S.A. Rosenberg, J. Ashwell, and A. Nussenzweig for their valuable discussions and intellectual input, Z. Franco, L.L. Parker, A. Navi, M. Langhan, R. Yoseph, G. Cafri, R. Somerville, D. Deniger, Y. Huang, A. Lalani, and P.H. Lee for helpful discussions in this project. We thank E. He for the illustrations. We thank S. Farid and A. Mixon in the flow cytometry facility of the Surgery Branch. We thank J. Shetty and B. Tran for help with sequencing work. All sequencing work was conducted at the Frederick National Laboratory for Cancer Research (FNLCR) at the CCR Sequencing Facility, NCI, NIH, Frederick. This work used the computational resources of the NIH HPC Biowulf cluster ( http://hpc.nih.gov ). Funding Information: The research was supported by the Intramural Research Program of the NCI, and by the Cancer Moonshot program for the Center for Cell-based Therapy at the NCI, NIH. The work was also supported by the Milken Family Foundation. The work presented here was entirely performed at the NIH. We thank S.A. Rosenberg, J. Ashwell, and A. Nussenzweig for their valuable discussions and intellectual input, Z. Franco, L.L. Parker, A. Navi, M. Langhan, R. Yoseph, G. Cafri, R. Somerville, D. Deniger, Y. Huang, A. Lalani, and P.H. Lee for helpful discussions in this project. We thank E. He for the illustrations. We thank S. Farid and A. Mixon in the flow cytometry facility of the Surgery Branch. We thank J. Shetty and B. Tran for help with sequencing work. All sequencing work was conducted at the Frederick National Laboratory for Cancer Research (FNLCR) at the CCR Sequencing Facility, NCI, NIH, Frederick. This work used the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). Conceptualization, D.G. S.J.P. and N.P.R.; Methodology, D.G. and S.J.P.; Investigation, D.G. S.J.P. A.N.H. S.K. N.Z. R.J.K. A.E. T.N.Y. C.M.K. S.K.V. R.E. M.A.B. J.H.P. Z.Y. L.J. D.C.P. and M.S.; Writing – Original Draft, D.G. S.J.P. and N.P.R.; Writing – Review & Editing, A.N.H. T.N.Y. C.M.K. M.A.B. R.E. J.H.P. Z.Y. S.K.V. R.J.K. A.E. M.S. and D.C.P.; Data Analysis and Curation, D.G. and S.J.P.; Funding Acquisition, N.P.R.; Resources, N.P.R. The work presented here was conducted entirely at NIH. S.K.V. R.J.K. and N.P.R. are employees of Lyell Immunopharma, and S.J.P. is an employee of NextCure Inc. A patent application has been filed based on some of the findings presented in this work. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020",
year = "2020",
month = jun,
day = "8",
doi = "10.1016/j.ccell.2020.05.004",
language = "English (US)",
volume = "37",
pages = "818--833.e9",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}