Epigenetic regulation of immune response

Antibodies blocking immune checkpoints offer a new therapeutic opportunity for patients with metastatic UC, but fewer than 20% will achieve a durable response. The overall poor response to chemotherapy and immunotherapy highlights a critical need to develop new, precision-based, therapies for metastatic or locally advanced UC that are ineligible or resistant to our current treatments.Metastatic urothelial cancer (UC) has the second worse survival of solid tumors with only 5% of patients alive at 5 yearsThe long-term goal of our research is to leverage the somatic alterations in chromatin modifier enzymes to develop precision therapies to enhance immune activation in UC. We genetically validated a smoking/carcinogen-induced mouse model of bladder cancer that develops the same somatic mutations identified in human bladder cancer. At a molecular level, we found that mutation of Kmt2c caused an imbalance of H3K27me3 at enhancer sites due to impaired recruitment of the COMPASS histone demethylase, Kdm6a resulting in unopposed EZH2 activityTo re-establish an “epigenetic balance”, we treated mice with an EZH2-inhibitor that caused regression of 80% of bladder tumors with a significant infiltration of CD3+ T cells and enhanced expression of T cell activation signatures. Based on these empiric findings, and potential impact to improve survival of patients with bladder cancer, the NCI and CTEP funded our Phase I/II trial of an EZH2-inhibitor (tazemetostat) combined with a PD1 inhibitor (pembrolizumab) through the Experimental Therapeutics Clinical Trial Network (ETCTN#10183, NCT0385447) While this trial is currently open and accruing, the mechanisms by which EZH2 regulates immune evasion in bladder cancer requires further investigation.