PROJECT SUMMARY This KOS proposal describes a five-year career development training program in cancer epigenetics and tumor immunology. Dr. Gabriel Griffin has completed clinical training in Hematopathology at Brigham and Women's Hospital and Harvard Medical School (HMS), and will embark on this research program with the goal of training for an independent laboratory-based career investigating basic mechanisms of immune regulation in cancer. In this training program, Dr Griffin will develop further expertise in the study of transposable elements and tumor immunity. and acquire new skills in the areas of genome topology. including the functional analysis of enhancer-promoter loops which will critically enable his future studies. His mentor, Dr. Bradley Bernstein (Chair of Cancer Biology at Dana-Farber Cancer Institute, Professor of Pathology at HMS, Director of the Epigenomics Program at the Broad Institute of MIT and Harvard) is an international leader in the field of cancer epigenomics with an excellent track record in mentoring trainees, including as independent laboratory-based faculty at major academic centers. Dr. Griffin has also assembled an Advisory Committee with complementary expertise in transposable elements (Dr. Burns), tumor immunology (Dr. Sharpe), and computational genomics (Dr. Van Allen), and extensive experience in mentoring physician-scientists to independent careers. Dr. Griffin will further supplement his training with didactic courses to deepen his scientific knowledge, leadership, and communication, and will regularly present his work at national and international meetings. The primary objective of Dr. Griffin's proposed research is to study epigenetic mechanisms of transposable element (TE) silencing and immune regulation in cancer cells. Dr. Griffin provides preliminary data indicating that lineage-specific re g PAX3 in melanoma} and conserved (e.g. CTCF) transcription factors (TFs} drive TE and immune gene activation in cancer cells following perturbation of SETDB1. a novel immunotherapy target identified in Dr Griffin's prior work (Griffin et al., Nature 2021). This proposal will examine the specific regulatory mechanisms that drive transcriptional responses in melanoma following SETDB1 loss, and will test the hypothesis that activation of latent TEs triggers consequent changes in regulatory circuitry and locus topology to drive immune activation. These studies will uncover fundamental mechanisms of epigenetic regulation of TEs and immune loci in melanoma. with broad potential applicability to other cancer types and the fields of of cancer epigenetics. tumor immunology. and immunotherapy.