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Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome [shEZH2]

ABSTRACT: To define the gene profile altered by EZH2 and H3K27me3 in response to IFNg, we performed several microarrays in primary ovarian cancer cells transfected with shEZH2 or treated with GSK126. We found that 155 and 124 genes were altered by shEZH2 and GSK126 treatment, respectively, and 20 genes were increased or decreased by both shEZH2 and GSK126 treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71870 | GEO | 2015/08/11

SECONDARY ACCESSION(S): PRJNA292385

REPOSITORIES: GEO

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Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome [shEZH2]

Project description:To define the gene profile altered by EZH2 and H3K27me3 in response to IFNg, we performed several microarrays in primary ovarian cancer cells transfected with shEZH2 or treated with GSK126. We found that 155 and 124 genes were altered by shEZH2 and GSK126 treatment, respectively, and 20 genes were increased or decreased by both shEZH2 and GSK126 treatment. Primary ovarian cancer cells were pretreated with GSK126, or transduced with a shEZH2 lentivirus, and stimulated with IFNg for 24 hours. RNA were isolated by Rneasy kit according to the manufacturer's protocol, and applied for affymetrix microarray at University of Michigan DNA Sequencing Core

2015-08-11 | E-GEOD-71870 | biostudies-arrayexpress

Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome [GSK126]

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Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome [GSK126]

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Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-08-11 | E-GEOD-71871 | biostudies-arrayexpress

Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome

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

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Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy.

Project description:Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.

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Global analyses of the effect of different cellular contexts on microRNA targeting (RNA-Seq)

Project description:RNA-seqs followed by miRNA transfections (miR-124 and miR-155) into four different cell lines( HeLa, HEK293, Huh7, and IMR90).

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Gene expression profiling of two DLBCL cell lines upon shRNA mediated knockdown of EZH2

Project description:We studied transcriptional changes by Affymetrix human microarrays in 2 DLBCL cell lines as a result of shRNA mediated knockdown of EZH2. In eukaryotes, epigenetic post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and is responsible for repressing target gene expression through methylation of histone H3 on lysine 27 (H3K27). Over-expression of EZH2 is implicated in tumorigenesis and correlates with poor prognosis in multiple tumor types. Recent reports have identified somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The Y641 residue is the most frequently mutated residue, with 22% of GCB (Germinal Cell B-cell) DLBCL and FL harboring mutations at this site. These lymphomas exhibit increased H3K27 tri-methylation (H3K27me3) due to altered substrate preferences of the mutant enzymes. However, it is unknown whether direct inhibition of EZH2 methyltransferase activity alone will be effective in treating lymphomas carrying activating EZH2 mutations. Herein, we demonstrate that GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and dramatically inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma. Pfeiffer and KARPAS-422 cells were treated with either shRNA targeting EZH2 (shEZH2) or a non targeting control (shNTC) for 10 days.

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Antigen experience shapes phenotype and function of memory Th1 cells.

Project description:Primary and secondary (boosted) memory CD8 T cells exhibit differences in gene expression, phenotype and function. The impact of repeated antigen stimulations on memory CD4 T cells is largely unknown. To address this issue, we utilized LCMV and Listeria monocytogenes infection of mice to characterize primary and secondary antigen (Ag)-specific Th1 CD4 T cell responses. Ag-specific primary memory CD4 T cells display a CD62L(lo)CCR7(hi) CD27(hi) CD127(hi) phenotype and are polyfunctional (most produce IFN?, TNF? and IL-2). Following homologous prime-boost immunization we observed pathogen-specific differences in the rate of CD62L and CCR7 upregulation on memory CD4 T cells as well as in IL-2+IFN?co-production by secondary effectors. Phenotypic and functional plasticity of memory Th1 cells was observed following heterologous prime-boost immunization, wherein secondary memory CD4 T cells acquired phenotypic and functional characteristics dictated by the boosting agent rather than the primary immunizing agent. Our data also demonstrate that secondary memory Th1 cells accelerated neutralizing Ab formation in response to LCMV infection, suggesting enhanced capacity of this population to provide quality help for antibody production. Collectively these data have important implications for prime-boost vaccination strategies that seek to enhance protective immune responses mediated by Th1 CD4 T cell responses.

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