| Literature DB >> 31442407 |
Matthew B Dong1, Guangchuan Wang2, Ryan D Chow3, Lupeng Ye2, Lvyun Zhu2, Xiaoyun Dai2, Jonathan J Park3, Hyunu R Kim2, Youssef Errami2, Christopher D Guzman4, Xiaoyu Zhou2, Krista Y Chen5, Paul A Renauer6, Yaying Du2, Johanna Shen5, Stanley Z Lam5, Jingjia J Zhou5, Donald R Lannin7, Roy S Herbst8, Sidi Chen9.
Abstract
CD8 T cells play essential roles in anti-tumor immune responses. Here, we performed genome-scale CRISPR screens in CD8 T cells directly under cancer immunotherapy settings and identified regulators of tumor infiltration and degranulation. The in vivo screen robustly re-identified canonical immunotherapy targets such as PD-1 and Tim-3, along with genes that have not been characterized in T cells. The infiltration and degranulation screens converged on an RNA helicase Dhx37. Dhx37 knockout enhanced the efficacy of antigen-specific CD8 T cells against triple-negative breast cancer in vivo. Immunological characterization in mouse and human CD8 T cells revealed that DHX37 suppresses effector functions, cytokine production, and T cell activation. Transcriptomic profiling and biochemical interrogation revealed a role for DHX37 in modulating NF-κB. These data demonstrate high-throughput in vivo genetic screens for immunotherapy target discovery and establishes DHX37 as a functional regulator of CD8 T cells.Entities:
Keywords: CD8 T cell; DHX37; T cell effector function; adoptive transfer; breast cancer; immunotherapy; in vivo CRISPR screen; lentiCRISPR; target discovery; tumor infiltration
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Year: 2019 PMID： 31442407 PMCID： PMC6719679 DOI： 10.1016/j.cell.2019.07.044
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582