Treatment of advanced melanoma with immunotherapy agents shows striking responses in some patients, however overall responses are low. In addition, a significant proportion of patients do not achieve a response at all. Hence, there is critical need to 1) identify biomarkers that may predict response and resistance to immune checkpoint blockade therapies and 2) Identify potential targets for combination treatment with immune check point blockade agents. We hypothesize that epigenetic processes in the tumors and immune cells play critical roles in governing the response to immune check point blockade. With our expertise in epigenomic technologies, we aim to 1) perform a systematic study of epigenomic content of tumors from responsive and non-responsive patients treated with anti-PD1 and 2) identify those epigenetic factors whose inhibition in combination with anti-PD1 treatment could enhance anti-tumor response of T-cells. Our study will provide insights into mechanisms of response and resistance to immune checkpoint blockade therapy.