Cell
Volume 178, Issue 5, 22 August 2019, Pages 1189-1204.e23
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Article
Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells

https://doi.org/10.1016/j.cell.2019.07.044Get rights and content
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Highlights

  • In vivo and in vitro genome-scale CD8 T cell CRISPR screen in immunotherapy contexts

  • Dhx37 knockout in CD8 T cells enhances adoptive transfer efficacy

  • Dhx37 modulates CD8 T cell activation, cytokine production, and cytotoxicity

  • DHX37 interacts with PDCD11 and influences NF-κB activity

Summary

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.

Keywords

in vivo CRISPR screen
CD8 T cell
tumor infiltration
DHX37
immunotherapy
target discovery
adoptive transfer
breast cancer
T cell effector function
lentiCRISPR

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19

These authors contributed equally

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