Systematic Immunotherapy Target Discovery Using Genome-Scale InVivo CRISPR Screens in CD8T Cells.

Abstract

CD8 Tcells play essential roles in anti-tumor immune responses. Here, we performed genome-scale CRISPR screens in CD8 Tcells directly under cancer immunotherapy settings and identified regulatorsof tumor infiltration and degranulation. The invivo screen robustly re-identified canonical immunotherapy targets such as PD-1 and Tim-3, along with genes that have not been characterizedin Tcells. The infiltration and degranulation screensconverged on an RNA helicase Dhx37. Dhx37 knockout enhanced the efficacy of antigen-specific CD8 Tcells against triple-negative breast cancer invivo. Immunological characterization in mouse and human CD8 Tcells revealed that DHX37 suppresses effector functions, cytokine production, and Tcell activation. Transcriptomic profiling and biochemical interrogation revealed arole for DHX37 in modulating NF-κB. These data demonstrate high-throughput invivo genetic screens for immunotherapy target discovery and establishes DHX37 as a functional regulator of CD8 Tcells.