Epigenetic Regulation of Immune Evasion in Bladder Cancer

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Bladder cancer is the fourth most common cancer in men and a significant burden for Veterans and the VHA due to the high frequency of recurrence and progression linked to smoking and exposure to deployment-related carcinogens. Less than 45% of patients with Stage IV bladder cancer survive more than a year in the VA suggesting the aggressive nature of metastatic urothelial tumors identified among Veterans. The primary cause of death from bladder cancer is resistance to therapy as these invasive carcinomas acquire cellular plasticity and stem cell-like properties from long-term changes in epigenetic regulators. In our first VA Merit Award, we first genomically validated a carcinogen-induced bladder cancer model that replicated smoking induced bladder cancer and shared the somatic alterations found in locally advanced bladder cancers. To re-establish an epigenetic balance, we then identified a significant decrease in carcinogen-induced bladder cancers in mice treated with an enzymatic EZH2-inhibitor. While bladder tumors decreased in size after treatment, we found a significant increase in the CD3+ T cell immune infiltrate associated with tumor regression. These results were rapidly translated into an NCI-sponsored clinical trial for patients with metastatic bladder cancer (ETCTN#10183). In this Phase I/II clinical trial, we are currently treating patients with an EZH2-inhibitor (tazemetostat) and a PD1 inhibitor (pembrolizumab). The PI of this application is the co-PI of the trial and despite clinical response there remains much to be investigated about the immunotherapy in bladder cancer and how a histone modifying complex (polycomb repressor complex 2, and EZH2) is involved in immune evasion. The long-term goal of our research is to investigate the molecular and epigenetic pathways associated with immune evasion of bladder cancer. By understanding these mechanisms, we may develop rational and novel therapeutics for Veterans with bladder cancer that combine precision targets and immunotherapy. Given this preliminary data, our central hypothesis is that EZH2 drives immune evasion by three distinct mechanisms that will be focus of this VA Merit proposal. In Aim 1 we will determine how EZH2 regulates antigen presentation by MHCI and MHCII to evade immune detection. In Aim 2, we evaluate how inhibition of EZH2 leads to recruitment of T cells to tumor microenvironment and in Aim 3 will focus on the action of EZH2 in Tregulatory cells that suppress an immune response. Through a multi-disciplinary collaboration we have demonstrated feasibility with our approach with rapid translation from bench to bedside. Successful completion of the studies described in this proposal will provide an innovative approach to both investigate the mechanisms involved in the evasion of the immune system of bladder cancer and potentially identify a novel therapeutic approach to treat bladder cancer.