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

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

PROVIDER: PRJNA692500 | 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.

2021-01-16 | GSE164949 | GEO

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

2021-01-16 | GSE164946 | GEO

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

2021-01-16 | GSE164947 | GEO

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

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

| PRJNA692497 | ENA

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

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

| PRJNA692498 | ENA

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

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

| PRJNA692499 | ENA

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

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

2021-01-16 | GSE164950 | GEO

4-1BB Co-stimulation Further Enhances Anti-PD-1-Mediated Reinvigoration of Exhausted CD39+ CD8 T Cells from Primary and Metastatic sites of Epithelial Ovarian Cancers

Project description:4-1BB Co-stimulation Further Enhances Anti-PD-1-Mediated Reinvigoration of Exhausted CD39+ CD8 T Cells from Primary and Metastatic sites of Epithelial Ovarian Cancers

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CAR T cells Overexpressing cJun Are Exhaustion-Resistant and Mediate Enhanced Antitumor Activity

Project description:CAR T cells mediate antitumor effects in a small subset of cancer patients, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system employing a tonically signaling CAR, which induces hallmarks of exhaustion described in other settings. Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs, and overexpression of numerous bZIP and IRF transcription factors that have been implicated in inhibitory activity. Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in numerous in vivo tumor models. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells and that engineering CAR T cells to overexpress c-Jun renders them exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.

2019-10-01 | GSE136796 | GEO

CAR T cells Overexpressing cJun Are Exhaustion-Resistant and Mediate Enhanced Antitumor Activity

2019-10-01 | GSE136891 | GEO