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BRD4 inhibition boosts the therapeutic effects of epidermal growth factor receptor-targeted chimeric antigen receptor T cells in glioblastoma

ABSTRACT: BRD4 inhibition boosts the therapeutic effects of epidermal growth factor receptor-targeted chimeric antigen receptor T cells in glioblastoma

PROVIDER: PRJNA730798 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14575544_1.fastq.gz	Fastqsanger.gz
	SRR14575544_2.fastq.gz	Fastqsanger.gz
	SRR14575545_1.fastq.gz	Fastqsanger.gz
	SRR14575545_2.fastq.gz	Fastqsanger.gz
	SRR14575546_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

BRD4 inhibition boosts the therapeutic effects of epidermal growth factor receptor-targeted chimeric antigen receptor T cells in glioblastoma

Project description:Glioblastoma (GBM) is the deadliest brain malignancy without effective treatments. Here, we report that epidermal growth factor receptor-targeted chimeric antigen receptor T cells (EGFR CAR-T) are effective in suppressing the growth of GBM cells in vitro and xenografts derived from GBM cell lines and patients in mice. However, mice soon acquire resistance to EGFR CAR-T cell treatment, limiting its potential use in the clinic. To find ways to improve the efficacy of EGFR CAR-T cells, we performed genomics and transcriptomics analysis for GBM cells incubated with EGFR CAR-T cells, and found that a large cohort of genes including immunosuppressive genes as well as enhancers in vicinity are activated. BRD4, an epigenetic modulator functioning on both promoter and enhancer, is required for the activation of these immunosuppressive genes. Accordingly, inhibition of BRD4 by JQ1 blocks the activation of these immunosuppressive genes. Combination therapy with EGFR CAR-T cells and JQ1 suppresses the growth and metastasis of GBM cells, and prolonged survival in mice. We demonstrate that transcriptional modulation by targeting epigenetic regulators could improve the efficacy of immunotherapy including CAR-T, providing a therapeutic avenue for treating GBM in the clinic.

2021-05-20 | GSE174617 | GEO

BRD4 is necessary for epidermal differentiation

Project description:BRD4 is an epigenetic reader known to bind to acetylated lysines on histones and transcription factors, and it has been implicated in recruiting transcriptional machinery to promote differentiation gene expression in multiple cellular contexts. This activity is dependant on proper BRD4 localization to active promoters and enhancers, which is dependant on a variety of factors including lineage determining transcription factors (LDTFs). We found BRD4 to be necessary for epidermal differentiation, during which it shares many chromatin binding sites with a variety of epidermal lineage-determining transcription factors (LDTF's). BRD4 also regulates a similar differentiation related transcriptional program with the epidermal LDTF KLF4.

2020-04-03 | GSE140992 | GEO

BRD4 is necessary for epidermal differentiation

Project description:BRD4 is necessary for epidermal differentiation

| PRJNA591618 | ENA

BRD4 inhibition boosts the therapeutic effects of epidermal growth factor receptor-targeted chimeric antigen receptor T cells in glioblastoma.

Project description:Glioblastoma (GBM) is the deadliest brain malignancy without effective treatments. Here, we reported that epidermal growth factor receptor-targeted chimeric antigen receptor T cells (EGFR CAR-T) were effective in suppressing the growth of GBM cells in vitro and xenografts derived from GBM cell lines and patients in mice. However, mice soon acquired resistance to EGFR CAR-T cell treatment, limiting its potential use in the clinic. To find ways to improve the efficacy of EGFR CAR-T cells, we performed genomics and transcriptomics analysis for GBM cells incubated with EGFR CAR-T cells and found that a large cohort of genes, including immunosuppressive genes, as well as enhancers in vicinity are activated. BRD4, an epigenetic modulator functioning on both promoters and enhancers, was required for the activation of these immunosuppressive genes. Accordingly, inhibition of BRD4 by JQ1 blocked the activation of these immunosuppressive genes. Combination therapy with EGFR CAR-T cells and JQ1 suppressed the growth and metastasis of GBM cells and prolonged survival in mice. We demonstrated that transcriptional modulation by targeting epigenetic regulators could improve the efficacy of immunotherapy including CAR-T, providing a therapeutic avenue for treating GBM in the clinic.

| S-EPMC8531146 | biostudies-literature

chimeric antigen receptor T cells with knockout

Project description:chimeric antigen receptor T cells with knockout

| PRJNA727540 | ENA

Targeting triple negative breast cancer with combination therapy of epidermal growth factor receptor-targeted chimeric antigen receptor T cell and CDK7 inhibitor

Project description:Targeting triple negative breast cancer with combination therapy of epidermal growth factor receptor-targeted chimeric antigen receptor T cell and CDK7 inhibitor

| PRJNA692427 | ENA

Targeting triple negative breast cancer with combination therapy of epidermal growth factor receptor-targeted chimeric antigen receptor T cell and CDK7 inhibitor

Project description:Epidermal growth factor receptor-targeted chimeric antigen receptor T cell (EGFR CAR-T) is potent and specific in suppressing triple-negative breast cancer (TNBC) cell growth in vitro and in vivo. However, a subset of mice soon acquired resistance, which limits the potential use of EGFR CAR-T. The aim of this study is to find a way to overcome the observed resistance. Transcriptomic analysis results revealed that EGFR CAR-T treatment led to the induction of a cohort of immunosuppressive genes, presumably through Interferon gamma (IFNγ signaling, in EGFR CAR-T-resistant TNBC tumors. EGFR CAR-T-induced immunosuppressive genes were found to be associated with EGFR CAR-T-activated enhancers and especially sensitive to THZ1, a CDK7 inhibitor, out of a panel of small molecules targeting epigenetic modulators screened. Accordingly, combination therapy of THZ1 and EGFR CAR-T suppressed immune resistance and tumor growth and metastasis in TNBC tumor models including human MDA-MB-231 cells-derived xenografts, TNBC patient-derived xenografts, and mouse EMT6 cells-derived allografts in mice. Taken together, we demonstrated that CAR-T therapy-induced immune resistance can be overcome by transcriptional modulation using epigenetic inhibitors, providing a therapeutic avenue for treating TNBC in the clinic.

2021-05-20 | GSE164902 | GEO

Epigenetic profiles of chimeric antigen receptor T cells

Project description:Epigenetic profiles of chimeric antigen receptor T cells

| PRJNA916209 | ENA

Bromodomain protein BRD4 is required for estrogen receptor-dependent transcription and enhancer activation [ChIP-seq]

Project description:The estrogen receptor-α (ERα) is a transcription factor which plays a critical role in controlling cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to induce or repress gene transcription. A deeper understanding of these transcriptional mechanisms may uncover novel therapeutic targets for ERα-dependent cancers. Here we show for the first time that BRD4 regulates ERα−induced gene expression by affecting elongation-associated phosphorylation of RNA Polymerase II (RNAPII P-Ser2) and histone H2B monoubiquitination (H2Bub1). Consistently, BRD4 activity is required for estrogen-induced proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide occupancy studies revealed an enrichment of BRD4 on transcriptional start sites as well as EREs enriched for H3K27ac and demonstrate a requirement for BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we further demonstrate that BRD4 occupancy correlates with active mRNA transcription and is required for the production of ERα-dependent enhancer RNAs (eRNAs). These results uncover BRD4 as a central regulator of ERα function and potential therapeutic target. ChIP-sequencing of BRD4, ERα and H2Bub1 in MCF7 cells treated with +/- estrogen treatment and or +/- JQ1 treatment in triplicates.

2014-07-10 | E-GEOD-55921 | biostudies-arrayexpress

Bromodomain protein BRD4 is required for estrogen receptor-dependent transcription and enhancer activation [RNA-Seq]

Project description:The estrogen receptor-M-NM-1 (ERM-NM-1) is a transcription factor which plays a critical role in controlling cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to induce or repress gene transcription. A deeper understanding of these transcriptional mechanisms may uncover novel therapeutic targets for ERM-NM-1-dependent cancers. Here we show for the first time that BRD4 regulates ERM-NM-1M-bM-^HM-^Rinduced gene expression by affecting elongation-associated phosphorylation of RNA Polymerase II (RNAPII P-Ser2) and histone H2B monoubiquitination (H2Bub1). Consistently, BRD4 activity is required for estrogen-induced proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide occupancy studies revealed an enrichment of BRD4 on transcriptional start sites as well as EREs enriched for H3K27ac and demonstrate a requirement for BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we further demonstrate that BRD4 occupancy correlates with active mRNA transcription and is required for the production of ERM-NM-1-dependent enhancer RNAs (eRNAs). These results uncover BRD4 as a central regulator of ERM-NM-1 function and potential therapeutic target. mRNA expression profiles of MCF7 cells treated with +/- estrogen treatment under negative control siRNA, BRD4 siRNA or JQ1 treatment, in duplicates.

2014-07-10 | E-GEOD-55922 | biostudies-arrayexpress

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