Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells

Publication date: 22 August 2019Source: Cell, Volume 178, Issue 5Author(s): Matthew B. Dong, Guangchuan Wang, Ryan D. Chow, Lupeng Ye, Lvyun Zhu, Xiaoyun Dai, Jonathan J. Park, Hyunu R. Kim, Youssef Errami, Christopher D. Guzman, Xiaoyu Zhou, Krista Y. Chen, Paul A. Renauer, Yaying Du, Johanna Shen, Stanley Z. Lam, Jingjia J. Zhou, Donald R. Lannin, Roy S. Herbst, Sidi ChenSummaryCD8 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.Graphical Abstract
Source: Cell - Category: Cytology Source Type: research

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