期刊
ISCIENCE
卷 4, 期 -, 页码 312-+出版社
CELL PRESS
DOI: 10.1016/j.isci.2018.05.021
关键词
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资金
- New Zealand Institute for Cancer Research Trust
- Maurice Wilkins Center for Molecular Biodiscovery
- Marsden Fund
- Healthcare Otago Charitable Trust
- Genesis Oncology Trust
- Maurice and Phyllis Paykel Trust
- Dunedin School of Medicine Bequest
- University of Otago Research Grant
- Melanoma Institute of Australia
- Australian National Health and Medical Research Council (NHMRC) [633004]
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-L1(CON)), 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 hencemelanoma's ability to evade anti-tumor immune responses. These results have implications for combining epigenetic therapy with immunotherapy.
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