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Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-small Cell Lung Cancer.

ABSTRACT: Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-small Cell Lung Cancer.

PROVIDER: PRJNA383805 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5464600_1.fastq.gz	Fastqsanger.gz
	SRR5464600_2.fastq.gz	Fastqsanger.gz
	SRR5464610_1.fastq.gz	Fastqsanger.gz
	SRR5464610_2.fastq.gz	Fastqsanger.gz
	SRR5464620_1.fastq.gz	Fastqsanger.gz

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Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer.

Project description:Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein, we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T-cell activation and improved function of antigen-presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+FOXP3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated antitumor immunity and demonstrate their therapeutic potential for treatment of NSCLC.Significance: Selective inhibition of HDACs and bromodomain proteins modulates tumor-associated immune cells in a manner that favors improved T-cell function and reduced inhibitory cellular mechanisms. These effects facilitated robust antitumor responses in tumor-bearing mice, demonstrating the therapeutic potential of combining these epigenetic modulators for the treatment of NSCLC. Cancer Discov; 7(8); 852-67. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 783.

| S-EPMC5540748 | biostudies-literature

Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-small Cell Lung Cancer.

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

2017-04-22 | GSE98049 | GEO

Systemically administered HMGN1 immunostimulatory peptide with anti-PD-L1 antibody exerts synergistic antitumor effects

Project description:Systemically administered HMGN1 immunostimulatory peptide with anti-PD-L1 antibody exerts synergistic antitumor effects

| PRJNA579156 | ENA

Histone deacetylase inhibitors cause the selective depletion of bromodomain containing proteins

Project description:Histone deacetylases (HDACs) and acetyltransferases control the epigenetic regulation of gene expression through modification of histone marks. Histone deacetylase inhibitors (HDACi) are small molecules that interfere with histone tail modification thus altering chromatin structure and epigenetically controlled pathways. They promote apoptosis in proliferating cells and are promising anti-cancer drugs. While some HDACis have already been approved for therapy and others are in different phases of clinical trials, the exact mechanism of action of this drug class remains elusive. Previous studies have shown that HDACis cause massive changes in chromatin structure but only moderate changes in gene expression. To which extent these changes manifest at the protein level has never been investigated on a proteome-wide scale. Here, we have studied HDACi-treated cells by large-scale mass spectrometry based proteomics. We show that HDACi treatment affects primarily the nuclear proteome and induces a selective decrease of bromodomain containing proteins (BCPs), the main readers of acetylated histone marks. By combining time-resolved proteome and transcriptome profiling, we show that BCPs are affected at the protein level as early as 12 hours after HDACi treatment and that their abundance is regulated by a combination of transcriptional and post-transcriptional mechanisms. Using gene silencing, we demonstrate that the decreased abundance of BCPs is sufficient to mediate important transcriptional changes induced by HDACi. Our data reveals a new aspect of the mechanism of action of HDACi that is mediated by an interplay between histone acetylation and the abundance of BCPs.

2015-03-18 | PXD001660 | Pride

Systemically administered HMGN1 immunostimulatory peptide with anti-PD-L1 antibody exerts synergistic antitumor effects

Project description:In this study, we explore a new combination therapy of anti-PD-L1 antibody with an immunostimulatory peptide derived from an alarmin high mobility group nucleosome binding protein 1 (HMGN1). Combination treatement of HMGN1 immunostimulatory peptide with anti-PD-L1 antibody exerted robust anti-tumor effects in Colon26 subtaneous murine model. To understand transcriptomic differences of immune cell population in the tumor-bearing mice after treated with single-agent or combination therapy of HMGN1 with anti-PD-L1 antibody, we performed transcriptome analysis on tumor tissue using 5’end Serial Analysis of Gene Expression (SAGE)-sequencing with an Ion 540 Chef kit, an Ion 540 Chip kit, and an Ion S5 Sequencer (Thermo Fisher Scientific).

2021-11-02 | GSE139291 | GEO

Combined targeting of the BRD4-NUT-p300 axis in NUT midline carcinoma by dual selective bromodomain inhibitor, NEO2734

Project description:NUT midline carcinoma (NMC) is a rare, aggressive subtype of squamous carcinoma that is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and NUT recruits the p300 histone acetyltransferse (HAT) to activate transcription of oncogenic target genes. BET selective bromodomain inhibitors have demonstrated on-target activity in NMC patients, but with limited efficacy. P300, like BRD4, contains a bromodomain. We show that combining selective p300/CBP and BET bromodomain inhibitors, GNE-781 and OTX015, respectively, induces synergistic inhibition of NMC growth. Treatment of NMC cells with the novel dual p300/CBP and BET bromodomain selective inhibitor, NEO2734, potently inhibits growth and induces differentiation of NMC cells in vitro; findings that correspond with potentiated transcriptional effects from combined BET and p300 bromodomain inhibition. In three disseminated NMC xenograft models, NEO2734 provided greater growth inhibition, with tumor regression and significant survival benefit seen in two of three models, compared with a lead clinical BET inhibitor or 'standard' chemotherapy.

2020-06-19 | GSE142481 | GEO

[RelA ChIP-seq]: Characterization of transcriptional and chromatin accessibility landscape of human bronchial epithelial cells treated with synergistic immunostimulatory ligands.

Project description:Lower respiratory tract infections remain a leading cause of death worldwide. The increasing prevalence of antibiotic-resistant respiratory pathogens has been a key driver of efforts to develop host-directed therapies that protect patients against pneumonia. Our laboratory has previously reported discovery of an immunostimulatory therapeutic comprised of a synthetic diacetylated lipopeptide, Pam2CSK4 (Pam2), and a class C CpG oligodeoxynucleotide, ODN M362 (ODN). When delivered by inhalation, this dyad protects synergistically against pneumonias caused by Gram-positive and -negative bacteria, seasonal and pandemic viruses, and multiple fungi. Protection is achieved by manipulating the immune defense response from lung epithelial cells. Here, we dissect the lung epithelial transcriptional response to explain the observed synergistic signaling, using RNA-seq and dual transcription factor ChIP-seq. We find cooperation of RelA and cJun following Pam2+ODN treatment that synergistically confers broad inducible resistance against respiratory pathogens. Specifically, transcription factor binding site (TFBS) analysis revealed that cJun occupancy at promoter regions of Pam2+ODN-induced genes facilitated increased RelA occupancy during differential expression, demonstrating cJUN-assisted loading of RelA as a key mechanism of the synergistic signaling events. Increased or decreased RelA occupancy at promoter sites dictated gene up- or down-regulation, respectively, while increased or decreased cJun occupancy at promoter sites directed synergistic or antagonistic gene expression patterns. Together, RelA and cJun work at promoter regions to control directionality and magnitude of gene expression after Pam2+ODN stimulation, rapidly reprograming the lung epithelial transcriptome to combat respiratory infections.

2025-06-15 | GSE299702 | GEO

[Bulk RNA-seq]: Characterization of transcriptional and chromatin accessibility landscape of human bronchial epithelial cells treated with synergistic immunostimulatory ligands.

2025-06-15 | GSE299678 | GEO

[cJun ChIP-seq]: Characterization of transcriptional and chromatin accessibility landscape of human bronchial epithelial cells treated with synergistic immunostimulatory ligands.

2025-06-15 | GSE299552 | GEO

Differential gene expression in neuroblastoma cells after treatment with vehicle control, JQ1, panobinostat, or combination of JQ1 and panobinostat

Project description:The bromodomain inhibitor JQ1 and the histone deacetylase inhibitor panobinostat induce synergistic anticancer effects We analyzed whether JQ1 and panobinostat synergistically modulate gene expression

2015-12-31 | GSE68690 | GEO

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