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Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells Mediate Enhanced Antitumor Activity

ABSTRACT: Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells Mediate Enhanced Antitumor Activity

PROVIDER: PRJNA692497 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13447200.fastq.gz	Fastqsanger.gz
	SRR13447201.fastq.gz	Fastqsanger.gz
	SRR13447202.fastq.gz	Fastqsanger.gz
	SRR13447203.fastq.gz	Fastqsanger.gz
	SRR13447204.fastq.gz	Fastqsanger.gz

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Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells Mediate Enhanced Antitumor Activity [RNA-seq]

Project description:T cell exhaustion limits immune responses against cancer and is a major cause of resistance to CAR-T cell therapeutics. Using a model wherein tonic CAR signaling induces hallmark features of exhaustion, we employed a drug-regulatable CAR to test the impact of transient cessation of receptor signaling (i.e. “rest”) on the development and maintenance of exhaustion. Induction of rest in exhausting or already-exhausted CAR-T cells resulted in acquisition of a memory-like phenotype, improved anti-tumor functionality, and wholescale transcriptional and epigenetic reprogramming. Similar results were achieved with the Src kinase inhibitor dasatinib, which reversibly suppresses CAR signaling. The degree of functional reinvigoration was proportional to the duration of rest and was associated with expression of transcription factors TCF1 and LEF1. This work demonstrates that transient cessation of CAR-T cell signaling can enhance anti-tumor potency by preventing or reversing exhaustion and challenges the paradigm that exhaustion is an epigenetically fixed state.

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Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells Mediate Enhanced Antitumor Activity [ATAC-seq]

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Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells Mediate Enhanced Antitumor Activity [ATAC-seq]

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Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells Mediate Enhanced Antitumor Activity [RNA-seq]

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Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells Mediate Enhanced Antitumor Activity [ATAC-seq, ChIP-seq]

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Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells Mediate Enhanced Antitumor Activity

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Krüppel-like factor 4 regulates the cytolytic effector function of exhausted CD8 T-cells [ATAC-Seq]

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Project description:Antitumor progenitor exhausted CD8 T cells are sustained with TCR engagement

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