Melanoma cells commonly express the surface protein PD-L1, which can help downplay T cell signaling and the anti-tumor immune response. Why this protein is constitutively expressed, or continuously active, in cancer remains poorly understood. New findings published in iScience now associate DNA methylation—or its lack thereof—in driving expression of PD-L1. The work, coming from a team led by the University of Otago and the University of Sidney, may have new implications on current therapy methods that affect methylation.

The team used reduced representation bisulfite sequencing (RRBS) to investigate DNA methylation at the whole genome scale. They found that melanoma cancer cell lines with constitutive PD-L1 were extensively hypomethylated, with DNA methylation levels much lower in comparison to the cell lines with only induced PD-L1.

This finding was further confirmed by treating melanoma cells with the drug decitabine, which inhibits DNA methyltransferase to hypomethylate DNA. As a result, PD-L1 expression increased accordingly.

"Our research provides evidence that it is the global loss of DNA methylation that regulates constitutive expression of the immune checkpoint PD-L1 in melanoma," said study first author Aniruddha Chatterjee.

The team also used RNA-Seq to find genes that were differentially expressed in cells with constitutive PD-L1. Among these genes were those involved with viral mimicry and immune response, such as DNMT3A.

New immune checkpoint inhibitor immunotherapies such as nivolumab and pembrolizumab have been approved to treat metastatic melanoma. However, some patients eventually develop resistance to such treatments.

"This work will contribute to selecting the best treatment option for patients, and also for developing new targets for epigenetic therapies," said senior co-author Michael Eccles. Eccles and his team are planning to develop a DNA methylation marker panel to predict the likelihood of melanoma patients responding to immunotherapy treatment.

From Biocompare