Epigenetic Regulation of Immune Evasion in Bladder Cancer

膀胱癌是男性第四大常见癌症，也是退伍军人和VHA的重大负担 由于与吸烟和暴露于部署相关的高频率复发和进展， 致癌物质。不到45%的IV期膀胱癌患者在VA存活超过一年 提示退伍军人中转移性尿路上皮肿瘤的侵袭性。主要原因 膀胱癌的死亡率是对治疗的抵抗，因为这些浸润性癌获得了细胞可塑性， 表观遗传调节因子的长期变化导致干细胞样特性。在我们的第一个VA优异奖，我们首先 在基因组学上验证了致癌物诱导的膀胱癌模型，该模型复制了吸烟诱导的膀胱癌。 癌症，并分享了在局部晚期膀胱癌中发现的体细胞改变。重新建立一个 表观遗传平衡，然后我们确定了致癌物诱导的小鼠膀胱癌显着减少 用酶促EZH 2抑制剂处理。虽然治疗后膀胱肿瘤的大小有所减少，但我们发现， 与肿瘤消退相关的CD 3 + T细胞免疫浸润的显著增加。这些结果 迅速转化为NCI申办的转移性膀胱癌患者临床试验（ETCTN#10183）。 在这项I/II期临床试验中，我们目前正在用EZH 2抑制剂（tazemetostat）和PD 1治疗患者。 抑制剂（派姆单抗）。本申请的PI是试验的共同PI，尽管存在临床应答 关于膀胱癌的免疫治疗以及组蛋白修饰 复合物（多梳阻遏物复合物2和EZH 2）参与免疫逃避。我们的长期目标是 研究的目的是探讨与膀胱免疫逃避相关的分子和表观遗传途径。 癌通过了解这些机制，我们可以为退伍军人开发合理的新疗法， 结合了联合收割机精确靶点和免疫疗法的膀胱癌。根据这些初步数据，我们的中央 假设EZH 2通过三种不同的机制驱动免疫逃避，这三种机制将是本VA优点的焦点 提议在目标1中，我们将确定EZH 2如何调节MHCI和MHCII的抗原呈递，以逃避 免疫检测在目标2中，我们评估了EZH 2的抑制如何导致T细胞向肿瘤的募集。 微环境和目标3将集中在EZH 2在T调节细胞中的作用， 反应通过多学科合作，我们已经证明了我们的方法的可行性， 从工作台到床边的快速翻译。成功完成本提案中所述的研究将 提供了一种创新的方法，既可以研究逃避免疫的机制， 膀胱癌系统，并潜在地鉴定治疗膀胱癌的新治疗方法。

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.