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

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Citations (Scopus)
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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-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.

Original languageEnglish
Pages (from-to)312-325
Number of pages42
JournaliScience
Volume4
DOIs
Publication statusPublished - 29 Jun 2018
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Cancer
  • Genetics
  • Genomics
  • Transcriptomics

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    Chatterjee, A., Rodger, E. J., Ahn, A., Stockwell, P. A., Parry, M., Motwani, J., ... Hersey, P. (2018). Marked global DNA hypomethylation is associated with constitutive PD-L1 expression in melanoma. iScience, 4, 312-325. https://doi.org/10.1016/j.isci.2018.05.021