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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164950 | GEO | 2021/01/16

REPOSITORIES: GEO

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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 restores functionality in exhausted CAR-T cells through epigenetic remodeling.

Project description:T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state.

| S-EPMC8049103 | biostudies-literature

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 [RNA-seq]

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

| PRJNA692500 | 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

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