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

Aniruddha Chatterjee; Euan J Rodger; Antonio Ahn; Peter A Stockwell; Matthew Parry; Jyoti Motwani; Stuart J Gallagher; Elena Shklovskaya; Jessamy Tiffen; Michael R Eccles; Peter Hersey

doi:10.1016/j.isci.2018.05.021

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

iScience. 2018 Jun 29:4:312-325. doi: 10.1016/j.isci.2018.05.021. Epub 2018 Jun 28.

Authors

Affiliations

¹ Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland, New Zealand. Electronic address: aniruddha.chatterjee@otago.ac.nz.
² Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland, New Zealand.
³ Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand.
⁴ Department of Mathematics & Statistics, University of Otago, 710 Cumberland Street, Dunedin 9054, New Zealand.
⁵ Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia.
⁶ Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland, New Zealand. Electronic address: michael.eccles@otago.ac.nz.
⁷ Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia. Electronic address: p.hersey@centenary.org.au.

Abstract

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-L1_IND), 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.

Keywords: Cancer; Genetics; Genomics; Transcriptomics.