Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy

Abdullah Al Emran; Aniruddha Chatterjee; Euan J Rodger; Jessamy C Tiffen; Stuart J Gallagher; Michael R Eccles; Peter Hersey

doi:10.1016/j.it.2019.02.004

Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy

Trends Immunol. 2019 Apr;40(4):328-344. doi: 10.1016/j.it.2019.02.004. Epub 2019 Mar 7.

Authors

Abdullah Al Emran¹, Aniruddha Chatterjee², Euan J Rodger³, Jessamy C Tiffen⁴, Stuart J Gallagher⁴, Michael R Eccles⁵, Peter Hersey⁶

Affiliations

¹ Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; These authors contributed equally.
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, 3A Symonds Street, Auckland, New Zealand; These authors contributed equally.
³ 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, 3A Symonds Street, Auckland, New Zealand.
⁴ Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia.
⁵ 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, 3A Symonds Street, Auckland, New Zealand; Senior author.
⁶ Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; Senior author. Electronic address: p.hersey@centenary.org.au.

PMID: 30853334
DOI: 10.1016/j.it.2019.02.004

Abstract

Methylation of DNA at CpG sites is the most common and stable of epigenetic changes in cancer. Hypermethylation acts to limit immune checkpoint blockade immunotherapy by inhibiting endogenous interferon responses needed for recognition of cancer cells. By contrast, global hypomethylation results in the expression of programmed death ligand 1 (PD-L1) and inhibitory cytokines, accompanied by epithelial-mesenchymal changes that can contribute to immunosuppression. The drivers of these contrasting methylation states are not well understood. DNA methylation also plays a key role in cytotoxic T cell 'exhaustion' associated with tumor progression. We present an updated exploratory analysis of how DNA methylation may define patient subgroups and can be targeted to develop tailored treatment combinations to help improve patient outcomes.

Keywords: DNA methylation; PD-L1; PD1; T cell exhaustion; biomarker; epigenetic remodeling; immune checkpoint blockade; melanoma; resistance; viral mimicry.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

B7-H1 Antigen / immunology
Cytokines / immunology
DNA Methylation / drug effects*
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / immunology
Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors*
Humans
Immunotherapy*
Melanoma / immunology*
Melanoma / pathology
Melanoma / therapy*

Substances

B7-H1 Antigen
CD274 protein, human
Cytokines
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein