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Global hypomethylation mediated changes regulate constitutive PD-L1 expression in melanoma

ABSTRACT: Global hypomethylation mediated changes regulate constitutive PD-L1 expression in melanoma

PROVIDER: PRJNA420852 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6339020.fastq.gz	Fastqsanger.gz
	SRR6339030.fastq.gz	Fastqsanger.gz
	SRR6339030_1.fastq.gz	Fastqsanger.gz
	SRR6339030_2.fastq.gz	Fastqsanger.gz
	SRR6339021.fastq.gz	Fastqsanger.gz

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Global hypomethylation mediated changes regulate constitutive PD-L1 expression in melanoma [RRBS]

Project description:PD-L1 is a ligand for the inhibitory PD1 receptor on T cells and its expression in some cancers inhibits anti-cancer immune response. In melanoma, PD-L1 expression is induced in response to immune stimuli but in a proportion of melanomas it is constitutively expressed. Factors that drive constitutive expression of PD-L1 are unknown. Here we performed genome-scale methylation analysis of six cell lines that constitutively express PD-L1 (PD-L1 positive, referred to as PD-L1CON) and six cell lines that only express PD-L1 after treatment with IFN- (PD-L1 negative, referred to as PD-L1IND)

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Global hypomethylation mediated changes regulate constitutive PD-L1 expression in melanoma [RRBS]

Project description:Global hypomethylation mediated changes regulate constitutive PD-L1 expression in melanoma [RRBS]

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Expression data in PD-L1 positive and PD-L1 negative human melanoma samples

Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.

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Expression data in PD-L1 positive and PD-L1 negative human melanoma samples

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Global hypomethylation mediated changes regulate constitutive PD-L1 expression in melanoma

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Marked Global DNA Hypomethylation Is Associated with Constitutive PD-L1 Expression in Melanoma.

Project description:Constitutive expression of the immune checkpoint, PD-L1, inhibits anti-tumor immune responses in cancer, although the factors involved in PD-L1 regulation are poorly understood. Here we show that loss of global DNA methylation, particularly in intergenic regions and repeat elements, is associated with constitutive (PD-L1CON), versus inducible (PD-L1IND), PD-L1 expression in melanoma cell lines. We further show this is accompanied by transcriptomic up-regulation. De novo epigenetic regulators (e.g., DNMT3A) are strongly correlated with PD-L1 expression and methylome status. Accordingly, decitabine-mediated inhibition of global methylation in melanoma cells leads to increased PD-L1 expression. Moreover, viral mimicry and immune response genes are highly expressed in lymphocyte-negative plus PD-L1-positive melanomas, versus PD-L1-negative melanomas in The Cancer Genome Atlas (TCGA). In summary, using integrated genomic analysis we identified that global DNA methylation influences PD-L1 expression in melanoma, and hence melanoma's ability to evade anti-tumor immune responses. These results have implications for combining epigenetic therapy with immunotherapy.

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