Epigenetic Regulation of Immune Evasion in Bladder Cancer

膀胱癌免疫逃避的表观遗传调控

基本信息

批准号：
10377393
负责人：
Joshua James Meeks
金额：
--
依托单位：
JESSE BROWN VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-10-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10377393
关键词：
Accounting Aftercare Antigen Presentation Award Bladder Bladder Neoplasm Blocking Antibodies CD3 Antigens CD8B1 gene Cancer Etiology Cancer Model Cancer Survivor Cancer Therapy Evaluation Program Carcinogens Carcinoma Cause of Death Cells Chromatin Chromatin Remodeling Factor Clinical Clinical Trials Clinical Trials Network Complex Data Detection Enhancers Enzymes Epigenetic Process Equilibrium Eragrostis Exposure to Frequencies Funding Genes Genetic Transcription Goals Histones Human Immune Immune Evasion Immune response Immune system Immunotherapy Impairment In Vitro Infiltration Interdisciplinary Study Investigation Investigational Therapies Link Lymphocyte Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Molecular Mus Mutation Nature Organoids Outcome PD-1 inhibitors Pathologic Pathway interactions Patients Phase I/II Clinical Trial Phase I/II Trial Polycomb Precision therapeutics Production Property Recurrence Regulation Repression Repressor Proteins Research Resistance Risk Role Site Smoking Solid Neoplasm Somatic Mutation T-Cell Activation T-Lymphocyte Trans-Activators Transcriptional Regulation Transitional Cell Carcinoma Translating Tumor-infiltrating immune cells Urothelium Veterans Work anti-PD1 therapy anti-tumor immune response base bench-to-bedside translation cancer cell checkpoint therapy chemokine chemotherapy epigenetic regulation epigenetic therapy histone demethylase immune activation immune checkpoint improved inhibitor innovation loss of function mutation lymph nodes men mouse model novel therapeutic intervention novel therapeutics pembrolizumab recruit refractory cancer response smoking exposure stem-like cell therapy resistant treatment strategy tumor tumor microenvironment

项目摘要

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.

膀胱癌是男性第四大常见癌症，对退伍军人和 VHA 来说是一个重大负担由于与吸烟和暴露于部署相关的环境相关的复发和进展频率很高致癌物质。在 VA，只有不到 45% 的 IV 期膀胱癌患者存活超过一年表明退伍军人中发现的转移性尿路上皮肿瘤具有侵袭性。主要原因膀胱癌死亡的主要原因是对治疗的抵抗，因为这些浸润性癌获得了细胞可塑性，并且表观遗传调节因子的长期变化产生类似干细胞的特性。在我们的第一个 VA 优异奖中，我们首先基因组验证了致癌物诱发的膀胱癌模型，该模型复制了吸烟诱发的膀胱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，然后我们发现致癌物诱发的小鼠膀胱癌显着减少用酶 EZH2 抑制剂处理。虽然膀胱肿瘤在治疗后尺寸减小，但我们发现与肿瘤消退相关的 CD3+ T 细胞免疫浸润显着增加。这些结果是迅速转化为 NCI 赞助的一项针对转移性膀胱癌患者的临床试验 (ETCTN#10183)。在此 I/II 期临床试验中，我们目前正在使用 EZH2 抑制剂（tazemetostat）和 PD1 治疗患者抑制剂（派姆单抗）。该申请的 PI 是该试验的共同 PI，尽管有临床反应关于膀胱癌的免疫疗法以及组蛋白修饰如何复合物（多梳阻遏复合物 2 和 EZH2）参与免疫逃避。我们的长期目标研究目的是调查与膀胱免疫逃避相关的分子和表观遗传途径癌症。通过了解这些机制，我们可以为退伍军人开发合理且新颖的疗法结合精准靶标和免疫治疗的膀胱癌。鉴于这些初步数据，我们的中央假设 EZH2 通过三种不同的机制驱动免疫逃避，这将是本 VA 优点的重点提议。在目标 1 中，我们将确定 EZH2 如何通过 MHCI 和 MHCII 调节抗原呈递以逃避免疫检测。在目标 2 中，我们评估了 EZH2 的抑制如何导致 T 细胞募集至肿瘤微环境和目标 3 将重点关注 EZH2 在调节性细胞中抑制免疫的作用回复。通过多学科合作，我们已经证明了我们的方法的可行性快速从工作台转移到床边。成功完成本提案中描述的研究将提供了一种创新方法来研究逃避免疫的机制膀胱癌系统，并有可能确定一种治疗膀胱癌的新治疗方法。