Dataset Information

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

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-?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.

SUBMITTER: Dong MB

PROVIDER: S-EPMC6719679 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Dong Matthew B MB Wang Guangchuan G Chow Ryan D RD Ye Lupeng L Zhu Lvyun L Dai Xiaoyun X Park Jonathan J JJ Kim Hyunu R HR Errami Youssef Y Guzman Christopher D CD Zhou Xiaoyu X Chen Krista Y KY Renauer Paul A PA Du Yaying Y Shen Johanna J Lam Stanley Z SZ Zhou Jingjia J JJ Lannin Donald R DR Herbst Roy S RS Chen Sidi S

Cell 20190801 5

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 enhance ...[more]

PMID: 31442407

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Project description:Cancer immunotherapy targets the interplay between immune and cancer cells. In particular, interactions between cytotoxic T lymphocytes (CTLs) and cancer cells, such as PD-1 (PDCD1) binding PD-L1 (CD274), are crucial for cancer cell clearance. However, immune checkpoint inhibitors targeting these interactions are effective only in a subset of patients, requiring the identification of novel immunotherapy targets. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening in either cancer or immune cells has been employed to discover regulators of immune cell function. However, CRISPR screens in a single cell type complicate the identification of essential intercellular interactions. Further, pooled screening is associated with high noise levels. Herein, we propose intercellular CRISPR screens, a computational approach for the analysis of genome-wide CRISPR screens in every interacting cell type for the discovery of intercellular interactions as immunotherapeutic targets. We used two publicly available genome-wide CRISPR screening datasets obtained while triple-negative breast cancer (TNBC) cells and CTLs were interacting. We analyzed 4825 interactions between 1391 ligands and receptors on TNBC cells and CTLs to evaluate their effects on CTL function. Intercellular CRISPR screens discovered targets of approved drugs, a few of which were not identifiable in single datasets. To evaluate the method's performance, we used data for cytokines and costimulatory molecules as they constitute the majority of immunotherapeutic targets. Combining both CRISPR datasets improved the recall of discovering these genes relative to using single CRISPR datasets over two-fold. Our results indicate that intercellular CRISPR screens can suggest novel immunotherapy targets that are not obtained through individual CRISPR screens. The pipeline can be extended to other cancer and immune cell types to discover important intercellular interactions as potential immunotherapeutic targets.

Dataset Information

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

Publications

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

Similar Datasets

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