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BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity

ABSTRACT: BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity

PROVIDER: PRJNA765317 | ENA |

REPOSITORIES: ENA

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BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity [RNA-Seq]

Project description:BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity [RNA-Seq]

| PRJNA765320 | ENA

BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity [ChIP-Seq, ATAC-Seq]

Project description:BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity [ChIP-Seq, ATAC-Seq]

| PRJNA765322 | ENA

BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity [RNA-Seq]

Project description:Targeting chromatin binding proteins and modifying enzymes can concomitantly affect tumor cell proliferation and survival, as well as enhance anti-tumor immunity and augment cancer immunotherapies. By screening a small molecule library of epigenetics-based therapeutics, BET bromodomain inhibitors (BETi) were identified as agents that sensitize tumor cells to the anti-tumor activity of CD8+ T-cells. BETi modulated tumor cells to be sensitized to the cytotoxic effects of the pro-inflammatory cytokine TNF. By preventing the recruitment of BRD4 to p65-bound cis-regulatory elements, BETi suppressed the induction of inflammatory gene expression, including the key NF-B target genes BIRC2 (cIAP1) and BIRC3 (cIAP2). Disruption of pro-survival NF-B signaling by BETi led to unrestrained TNF-mediated activation of the extrinsic apoptotic cascade and tumor cell death. Administration of BETi in combination with T-cell bispecific (TCB) antibodies increased bystander killing of tumor cells and enhanced tumor growth inhibition in vivo in a TNF-dependent manner. This novel epigenetic mechanism of immunomodulation may guide future use of BETi as adjuvants for immune oncology agents.

2021-09-24 | GSE184589 | GEO

BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity [ChIP-Seq, ATAC-Seq]

2021-09-24 | GSE184591 | GEO

BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity

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

2021-09-24 | GSE184592 | GEO

Pharmacologic modulation of RNA splicing enhances anti-tumor immunity.

Project description:Pharmacologic modulation of RNA splicing enhances anti-tumor immunity.

| PRJNA683080 | ENA

Epigenetic priming enhances anti-tumor immunity in resistant ovarian cancer

Project description:Epigenetic priming enhances anti-tumor immunity in resistant ovarian cancer

| PRJNA778066 | ENA

Cyclin-dependent kinase 9 is a therapeutic target for anti-TNF resistant inflammatory bowel disease

Project description:The treatment of auto-inflammatory diseases is often limited by resistance to single cytokine blockade, primarily anti-TNF antibodies. This is a particularly important cause of treatment failure in inflammatory bowel disease (IBD). The transcription factor T-bet is a critical regulator of intestinal homeostasis and is genetically linked to mucosal inflammation by causal variation in its binding sites. However, transcription factors such as T-bet are difficult to target therapeutically. Using CDK9 inhibitors, we show that modulation of P-TEFb (cyclinT1/CDK9), a transcriptional elongation factor downstream of T-bet, potently represses genes responsible for pro-inflammatory signalling, and in particular genes regulated by T-bet. Remarkably, CDK9 inhibition targets genes that are highly expressed in anti-TNF resistant IBD and that predict non-response to anti-TNF therapy. Collectively, our findings reveal CDK9 as a potential target in anti-TNF resistant IBD, which has the potential for rapid translation to the clinic.

2022-06-17 | GSE172372 | GEO

BET bromodomain inhibition

Project description:BET bromodomain inhibition

| PRJNA379010 | ENA

Epigenetic targeting of immunocheckpoint PD-L1 by BET bromodomain inhibition

Project description:Epigenetic regulators have emerged as exciting targets for cancer therapy. Additionally, restoration of antitumor immunity by blocking the PD-L1 signaling using antibodies has proven to be beneficial in cancer therapy. Here we show that BET bromodomain inhibition suppresses PD-L1 expression and restores antitumor immunity in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of antitumor cytotoxic T cells. Together, these data demonstrate an epigenetic approach to block PD-L1 signaling to restore antitumor immunity. Given the fact that BET inhibitors have been proven safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a novel treatment strategy for targeting PD-L1 expression.

2016-10-17 | GSE81698 | GEO

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