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

被引：124

作者：

Gurusamy, Devikala ^{[1
,2
]}

Henning, Amanda N. ^{[1
,2
]}

Yamamoto, Tori N. ^{[1
,2
,3
]}

Yu, Zhiya ^{[1
,2
]}

Zacharakis, Nikolaos ^{[1
]}

Krishna ^{[1
]}

Kishton, Rigel J. ^{[1
,2
,5
]}

Vodnala, Suman K. ^{[1
,2
,5
]}

Eidizadeh, Arash ^{[1
,2
]}

Jia, Li ^{[1
]}

Kariya, Christine M. ^{[1
,2
]}

Black, Mary A. ^{[1
,2
]}

Eil, Robert ^{[1
,2
]}

Palmer, Douglas C. ^{[1
,2
]}

Pan, Jenny H. ^{[1
,2
]}

Sukumar, Madhusudhanan ^{[1
,2
]}

Patel, Shashank J. ^{[1
,2
,4
]}

Restifo, Nicholas P. ^{[1
,2
,3
,5
]}

机构：

[1] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA

[2] NIH, Ctr Cell Based Therapy, Ctr Canc Res, Bethesda, MD 20892 USA

[3] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA

[4] NextCure Inc, Beltsville, MD 20705 USA

[5] Lyell Immunopharma, San Francisco, CA 94080 USA

来源：

CANCER CELL | 2020年 / 37卷 / 06期

关键词：

TUMOR-INFILTRATING LYMPHOCYTES; T-CELLS; EXPANSION; ACTIVATION; REGULATOR; RECEPTOR; THERAPY; PATHWAY; GENES; CD19;

D O I：

10.1016/j.ccell.2020.05.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：818 / +

页数：25

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