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Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction [scRNA-seq]

ABSTRACT: Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction [scRNA-seq]

PROVIDER: PRJNA963197 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24352040_1.fastq.gz	Fastqsanger.gz
	SRR24352040_2.fastq.gz	Fastqsanger.gz
	SRR24352041_1.fastq.gz	Fastqsanger.gz
	SRR24352041_2.fastq.gz	Fastqsanger.gz
	SRR24352042_1.fastq.gz	Fastqsanger.gz

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Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction

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Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction [scRNA-seq]

Project description:Chimeric antigen receptor (CAR) engineered T cells often fail to enact effector functions after infusion into patients. Understanding the biological pathways that lead CAR T cells to failure is of critical importance in the design of more effective therapies. We developed and validated an in vitro model that drives T cell dysfunction by chronic CAR stimulation and interrogated how CAR costimulatory domains contribute to T cell failure. We found that dysfunctional CD28-based CARs targeting CD19 bear hallmarks of classical T cell exhaustion while dysfunctional 41BB-based CARs are phenotypically, transcriptionally and epigenetically distinct. We confirmed activation of this unique transcriptional program in CAR T cells that failed to control clinical disease. Further, we demonstrate that 41BB-dependent activation of the transcription factor FOXO3 is a significant contributor to this dysfunction and disruption of FOXO3 significantly improves 41BB-based CAR T cell function. These findings identify that chronic activation of 41BB leads to novel state of T cell dysfunction that can be alleviated by genetic modification of FOXO3.

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Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction [ATAC-seq]

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Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction

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Gene expression in self-activating CAR-T cells with CD28 or 4-1BB costimulatory domains.

Project description:We observed self-activation of SKM-CAR-T cells which target novel mesothelioma antigen. CAR-T with CD28 costimulatory domain showed signs of exhaustion while those with 4-1BB costimulatory domain did not. Changes in the gene expression by substituting CD28 co-stimulatory domain to 4-1BB co-stimulatory domain was investigated.

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Transient mTOR inhibition rescues 4-1BB-CAR-Tregs from tonic signal-induced dysfunction

Project description:RNAseq analysis of human CAR-Tregs, bearing CD28 or 4-1BB as a costimulatory domains, initially isolated (before engineering) from peripheral blood of healthy donors

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Gene expression in self-activating CAR-T cells with CD28 or 4-1BB costimulatory domains.

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