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Systematic identification of immunotherapy targets using genome-scale in vivo CRISPR screens in CD8+ cytotoxic T cells [RNA-Seq]

ABSTRACT: Systematic identification of immunotherapy targets using genome-scale in vivo CRISPR screens in CD8+ cytotoxic T cells [RNA-Seq]

PROVIDER: PRJNA549474 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9320490_1.fastq.gz	Fastqsanger.gz
	SRR9320490_2.fastq.gz	Fastqsanger.gz
	SRR9320491_1.fastq.gz	Fastqsanger.gz
	SRR9320491_2.fastq.gz	Fastqsanger.gz
	SRR9320492_1.fastq.gz	Fastqsanger.gz

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Systematic identification of immunotherapy targets using genome-scale in vivo CRISPR screens in CD8+ cytotoxic T cells [scRNA-Seq]

Project description:CD8+ cytotoxic T cells play essential roles in anti-tumor immune responses. Here, we performed in vivo screens in CD8+ T cells and identified regulators of tumor infiltration and killing, which are directly relevant to cancer immunotherapy. Unlike in vitro screens, 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 cancer in vivo. Immunological characterization in mouse and human CD8+ T cells revealed that DHX37 suppresses effector function, cytokine production, and T cell activation. Transcriptomic profiling and biochemical interrogation revealed a role for DHX37 in modulating the NF-kB pathway. These data demonstrated the power of high-throughput in vivo genetic screens for immunotherapy target discovery, and uncovered DHX37 as a functional regulator of CD8+ T cells.

2019-08-22 | GSE132959 | GEO

Systematic identification of immunotherapy targets using genome-scale in vivo CRISPR screens in CD8+ cytotoxic T cells [RNA-Seq]

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Systematic identification of immunotherapy targets using genome-scale in vivo CRISPR screens in CD8+ cytotoxic T cells [scRNA-Seq]

Project description:Systematic identification of immunotherapy targets using genome-scale in vivo CRISPR screens in CD8+ cytotoxic T cells [scRNA-Seq]

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Systematic identification of immunotherapy targets using genome-scale in vivo CRISPR screens in CD8+ cytotoxic T cells

Project description:This SuperSeries is composed of the SubSeries listed below.

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Project description:A number of reports have demonstrated that tumor-intrinsic mechanisms of resistance, such as the loss of genes critical for antigen presentation and inflammatory responses, along with the activation of various cellular signaling cascades, can limit the efficacy of immunotherapy. Strategies to sensitize tumor cells to immunotherapy may overcome some resistance mechanisms, but identifying therapeutic targets has remained challenging. Here, we integrate a two-cell type (2CT) whole-genome CRISPR-Cas9 screen with dynamic transcriptional profiling of the tumor/T cell interaction to comprehensively identify tumor genes that are induced to promote tumor survival. We assessed the therapeutic potential of pharmacological inhibition of these and other top CRISPR identified targets as combinatorial targets to improve the efficacy of tumor destruction by T cells.

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Project description: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.

| S-EPMC6719679 | biostudies-literature

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