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

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 wi...

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Bibliographic Details
Published iniScience Vol. 4; pp. 312 - 325
Main Authors Chatterjee, Aniruddha, Rodger, Euan J., Ahn, Antonio, Stockwell, Peter A., Parry, Matthew, Motwani, Jyoti, Gallagher, Stuart J., Shklovskaya, Elena, Tiffen, Jessamy, Eccles, Michael R., Hersey, Peter
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 29.06.2018
Elsevier
Subjects
Cancer
Genetics
Genomics
Transcriptomics
Genetics
Transcriptomics
Genomics
Cancer
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Summary: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. [Display omitted] •Global DNA hypomethylation in melanoma promotes constitutive PD-L1 expression•Transcriptomic up-regulation accompanies constitutive PD-L1 expression in melanoma•Constitutive PD-L1 is associated with reduced DNMT3A expression and viral mimicry•DNA methylation inhibitor treatment of melanoma cells increases PD-L1 expression Genetics; Genomics; Cancer; Transcriptomics
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These authors contributed equally
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ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2018.05.021