Dr Aniruddha Chatterjee, a senior researcher fellow at the University of Otago’s pathology department has jointly led a study that found a modification to a protein on cancer cell surfaces that can impact on the success of immune therapy drugs such as nivolumab (Opdivo) and pembrolizumab (Keytruda).

The findings of Chatterjee and Otago research partner Professor Mike Eccles and Professor Peter Hersey from the University of Sydney were published in the international journal iScience today and shed light on why some of the new immune checkpoint inhibitor drug therapies may not work for some patients.

Drugs like Opdivo and Keytruda, which were approved in New Zealand in 2016 to treat metastatic melanoma, have been heralded as a significant advancement in cancer treatment, but while very effective for some melanoma patients, for others the therapies do not work at all.

A key component of the mechanism that makes immunotherapy work is a protein on the surface of cancer cells called PD-L1, which can potentially be either receptive or block immunotherapy drugs.

The Otago researchers found that an epigenetic modification – that is, a modification that doesn’t change the DNA sequence of a gene but changes its expression – known as  DNA methylation influences how PD-L1 is expressed on the cancer cell surface.

Dr Chatterjee, who last year was awarded a Rutherford Discovery Fellowship to study the epigenetics of metastasis, said melanoma is a global problem, but is particularly relevant in New Zealand where we have the highest rates of the disease.

Oncologist Chris Jackson, who is a researcher for the University of Otago’s Centre for Translational Cancer Research but is not involved in this project, explains biomarkers are tools to select which patients benefit from which cancer therapies.

“Currently, there are no reliable biomarkers for predicting benefit from immune therapy in melanoma and these are desperately needed in the clinic,” said Jackson.

“Biomarkers would help choose which patients 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.”

However, 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”, said Jackson.

Dr Chatterjee said 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.

The Health Research Council this month awarded $1,198,714 to the researchers to continue their work on patients in New Zealand over the next three years. Professor Eccles said they plan to develop a DNA methylation marker panel that predicts the likelihood of melanoma patients responding to immunotherapy treatment.

“This work will contribute to selecting the best treatment option for patients, and also for developing new targets for epigenetic therapies.”

There is currently no robust biomarker able to predict patient response and also relatively little understanding of 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,” Dr Chatterjee explained.

The findings have been heralded by the researchers’ peers internationally as highly novel and a major advance in understanding melanoma biology.

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