Background and the scientific challenge

For the first time in history, the word “cure” can now be used for patients with metastatic melanoma. For decades, treatment was restricted to a chemotherapy drug that do not extend patient survival. However, a major shift in treatment arose when it was found that melanoma cells frequently express a protein called PD-L1 to inhibit immune cells in order to grow undetected in the body. This was followed by discovery of novel drugs that block PD-L1 interaction which in turn reawakens the immune attack. Patients who respond to these immunotherapeutic drugs become free of melanoma and have long-term survival.

In 2016, after ongoing public pressure, the NZ government approved funding of these immunotherapeutic drugs. However now the major issue is that these drugs only work in a small proportion (approximately 30%) of metastatic melanoma patients. Many research groups worldwide have heavily focused on understanding why only a fraction of patients respond. Until this end, the greatest barrier has been the lack of understanding of how PD-L1 is expressed in melanoma cells. Thus, there is a critical need to understand the molecular mechanisms that lead to PD-L1 expression in melanoma. Multiple research groups, including ours, have found DNA mutations do not play a role in PD-L1 expression. Thus, our group hypothesized epigenetics have a role in regulating PD-L1 levels. DNA methylation is a fundamental epigenetic mechanism that plays an indispensable role in switching genes on or off and determine cellular function. Generally, DNA methylation silences gene expression.

Our discovery

To address the role of epigenetics in regulating PD-L1, we characterized 12 patient-derived melanoma cell lines in which 6 permanently expresses PD-L1 and 6 that do not express PD-L1. From these 12 samples we generated a genome-wide map for both DNA methylation and gene expression using next generation sequencing methods.