The research findings by University of Otago shed much-needed light on why new immune checkpoint inhibitor therapies such as nivolumab and pembrolizumab- approved by the New Zealand Government for the first time in 2016 to treat metastatic melanoma- do not work on many patients.

The new immunotherapeutic drugs herald a significant advancement in a cure for cancer. But while they can be effective for some melanoma patients, for others the therapies do not work at all, and most eventually become resistant to immunotherapy treatments. One of the key components of the immune checkpoint mechanism is a protein on the surface of cancer cells called PD-L1 which can potentially be receptive to or block immunotherapy.

The researchers were able to show that epigenetic modification-- DNA modifications that do not directly alter the DNA sequence but instead change the frequency by which a cell uses specific genes -- specifically DNA methylation, influences whether PD-L1 is expressed on the cancer cell surface.

"Currently, there are no reliable biomarkers for predicting benefit from immune therapy in melanoma and these are desperately needed in the clinic," said a researcher Chris Jackson. Jackson added that biomarkers help in choosing patients who are likely to benefit and who are not. "Many groups worldwide are searching for immune-therapy biomarkers and this Otago discovery of an epigenetic marker appears very promising," he added.

Jackson believes the findings will now need to be tested in people with melanoma undergoing treatment to see if this test can make it "from the bench to the bedside." Another lead researcher Aniruddha Chatterjee says the findings suggest epigenetic therapies could be used in clinical trials in combination with immunotherapy in melanoma to treat patients. However, further trials would be needed before this could become a possibility.

Due to non-availability of robust biomarkers, it is difficult to predict a patient's response and also a relatively lesser understanding on the basis for resistance to immunotherapy treatment of melanoma. There is a global effort to unlock the secrets behind resistance to immunotherapy and the Otago researchers believe they may have uncovered a key piece of the puzzle.

DNA methylation is an epigenetic mechanism that plays a key role in switching genes "on" or "off" and helps to determine cellular function. Generally, DNA methylation silences gene expression and has been implicated in cancer. "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," Chatterjee said. The findings have been heralded by the researchers' peers internationally as "highly novel" and a major advance in understanding melanoma biology. The study appears in iScience journal.