Epigenetic Regulation of Immune Evasion in Bladder Cancer

膀胱癌是男性第四常见的癌症，对退伍军人和VHA来说是一个沉重的负担 由于吸烟和暴露在与部署有关的环境中，复发和进展的频率很高 致癌物质。不到45%的IV期膀胱癌患者在退伍军人事务部存活超过一年 提示在退伍军人中发现的转移性尿路上皮肿瘤具有侵袭性。主要原因是 膀胱癌的死亡原因是抵抗治疗，因为这些浸润性癌获得了细胞可塑性和 来自表观遗传调节器长期变化的干细胞样特性。在我们的第一个VA功勋奖中，我们首先 复制吸烟诱导膀胱癌的致癌物诱导膀胱癌模型的基因组验证 并分享了在局部晚期膀胱癌中发现的躯体变化。要重新建立一个 表观遗传平衡，然后我们发现致癌物诱导的小鼠膀胱癌显著减少 用酶促EZH2抑制剂处理。虽然治疗后膀胱肿瘤的大小有所缩小，但我们发现 CD3+T细胞免疫浸润显著增加与肿瘤消退相关。这些结果是 迅速转化为美国国立卫生研究院赞助的转移性膀胱癌患者的临床试验(ETCTN#10183)。 在这项I/II期临床试验中，我们目前正在使用EZH2抑制剂(TazemTostat)和PD1治疗患者 抑制剂(培溴利珠单抗)。此应用程序的PI是试验的共同PI，尽管有临床反应 关于膀胱癌的免疫治疗以及组蛋白如何修饰仍有许多有待研究的地方 复合体(多梳抑制物复合体2和EZH2)参与免疫逃避。我们的长期目标是 研究旨在探讨与膀胱免疫逃避有关的分子和表观遗传途径。 癌症。通过了解这些机制，我们可能会为退伍军人开发合理的新疗法。 结合精确靶点和免疫疗法的膀胱癌。鉴于这一初步数据，我们的中央 假设是EZH2通过三种不同的机制驱动免疫逃避，这将是这一VA优点的重点 求婚。在目标1中，我们将确定EZH2如何调节MHCI和MHCII的抗原提呈以逃避 免疫检测。在目标2中，我们评估了抑制EZH2是如何导致T细胞向肿瘤募集的 微环境和目标3将重点放在EZH2在抑制免疫的T调节细胞中的作用 回应。通过多学科协作，我们已经证明了我们的方法的可行性 从长凳到床边的快速转换。成功完成本提案中所述的研究将 提供了一种创新的方法来研究免疫逃避所涉及的机制 目前，该公司正在研究膀胱癌的治疗系统，并有可能确定一种治疗膀胱癌的新方法。

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.