Journal
CELL
Volume 178, Issue 5, Pages 1189-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2019.07.044
Keywords
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Categories
Funding
- Yale SBI/Genetics Startup Fund
- NIH/NCI [DP2CA238295-01, R01CA231112-01, R33CA225498-01A1, RF1DA048811, U54CA209992-8697, P50CA196530-A10805, P50CA121974-A08306]
- Damon Runyon Dale Frey Award [DFS-13-15]
- Melanoma Research Alliance [412806, 16-003524]
- St-Baldrick's Foundation [426685]
- Breast Cancer Alliance
- Cancer Research Institute (CLIP)
- AACR [499395, 17-20-01-CHEN]
- Mary Kay Foundation [01781]
- V Foundation [V2017-022]
- Ludwig Family Foundation
- DoD [W81XWH-17-1-0235]
- Sontag Foundation (Chen DSA)
- Chenevert Family Foundation
- Yale SPORE in Lung Cancer [P50CA196530]
- Yale MSTP training grant from NIH [T32GM007205]
- Yale PhD training grant from NIH [T32GM007499]
- CRI Irvington Postdoctoral Fellowship
- RJ Anderson Postdoctoral Fellowship
- C Revson Postdoctoral Fellowship
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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-kappa B. These data demonstrate high-throughput in vivo genetic screens for immunotherapy target discovery and establishes DHX37 as a functional regulator of CD8 T cells.
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