PROJECT 2: PROJECT SUMMARY Despite remarkable progress in treating advanced melanoma, the prognosis remains variable. Specifically, nearly all metastatic melanoma patients develop resistance to targeted therapy with time, while approximately half do not respond to immunotherapy. These challenges highlight an urgent need to develop novel therapeutic interventions, improve current treatments, and develop biomarkers that predict response. Emerging evidence suggests that epigenetic regulators KDM5B and SETDB1 as therapeutic targets and endogenous retroelements (REs) as biomarkers of response to immunotherapies. Our long-term goal is to translate our findings of novel mechanisms involved in melanoma progression to the clinic. The objectives of this project are to dissect the cellular mechanisms by which KDM5B and SETDB1 loss induce anti-tumor immunity, develop biomarkers to predict response to immune checkpoint inhibitors, and to evaluate the therapeutic potential of depleting KDM5B in melanoma. Our central hypotheses are that KDM5B and SETDB1 targeting de-repress the expression of retroelements to initiate robust anti-melanoma immune responses, and retroelements can be harnessed to predict response to immunotherapy. The hypothesis is supported by previous studies as well as our own preliminary data from patient-derived melanomas and preclinical melanoma models. The rationale is that better understanding of how KDM5B and SETDB1 suppress melanoma growth and anti-tumor immune responses will result in new and innovative approaches to treat melanoma. The hypotheses will be tested in three Specific Aims: 1) Dissect the mechanisms of immune responses induced by KDM5B and SETDB1 loss; 2) Evaluate the therapeutic potential of depleting KDM5B in melanoma; 3) Evaluate REs suppressed by KDM5B and SETDB1 as predictive biomarkers in human melanoma. The proposed research is conceptually, technically, and clinically innovative, because it aims to examine the therapeutic potential of KDM5B depletion using “first in class” KDM5B degraders, and to evaluate RE levels as novel predictive biomarker for response to immunotherapy. The results from these studies could impact the treatment of patients with melanoma and increase our understanding of the factors that regulate anti-tumor immune responses.