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Aggressive prostate cancer of African Americans is correlated with regulation of Immunoregulatory Genes in stroma

非裔美国人的侵袭性前列腺癌与基质中免疫调节基因的调节相关

基本信息

批准号：
10593179
负责人：
Farah Bakhshian Rahmatpanah
金额：
$ 34.64万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-03 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593179
关键词：
African American African American population American Antibodies Antineoplastic Agents Biological Assay Blood Cancer Burden Cancer Patient Caring Cell physiology Cells Coculture Techniques Colorectal Cancer DNA Methylation Dendritic Cells Disease Disease Outcome Disease Progression Dose Double-Stranded RNA Endogenous Retroviruses Enrollment Epigenetic Process Epithelium European Exposure to Fibroblasts Genes Growth and Development function Human Genome IRF3 gene Immune Immune response Immune system Immunohistochemistry Individual Interferons Knowledge Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Medical Methyltransferase Outcome Pathway interactions Patients Pharmacotherapy Phenotype Production Prognosis Prostate Prostate Cancer therapy Proteins RNA Race Radical Prostatectomy Recurrent disease Regulation Relapse Resources Role Sampling Socioeconomic Factors Solid Neoplasm Stains Stromal Cells T cell response T-Cell Activation Testing Therapeutic Intervention Time Tissue Microarray Tissues Treatment-Related Cancer Viral advanced prostate cancer anti-tumor immune response falls immune clearance immunoregulation improved outcome inhibitor male malignant breast neoplasm men monocyte neoplastic cell new therapeutic target novel novel therapeutics nucleotide analog preservation prognostic prostate cancer cell prostate cancer progression protein biomarkers protein expression racial difference recruit transcription factor tumor tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT African-Americans (AA) present with overall more advanced prostate cancer (PCa) than European Americans (EA). Even when socioeconomic factors are controlled for, AA have a worse prognosis than EA at the same stage of cancer. Furthermore, 35% of AA patients assigned to active surveillance rather than radical treatment eventually have to undergo treatment due to disease progression, compared with only 15% of EA patients. In preliminary studies, we have observed higher activation of an entire anti-viral immune response pathway in tumor-adjacent stroma of EA PCa patients when compared to AA. This pathway begins with the activation of endogenous retroviruses, which are ubiquitous in the human genome but are normally DNA methylated and inactive. In EA prostate cancer stroma, ERVs are activated, with higher expression and lower DNA methylation than in AA. When activated, ERVs produce dsRNA that, in turn, activates type 1 interferons (IFNs), which are also higher in EA than in AA prostate cancer stroma. IFNs then activate expression of interferon-stimulated genes (ISGs), which are more highly expressed in EA but not AA stroma. Finally, we see higher expression levels of markers of activated dendritic cells (DCs) in EA but not AA stroma. DC are immune system cells that are an ultimate target of the IFNs and can be anti-tumor. We hypothesize that epigenetic control of anti-viral immune response pathways in prostate stromal cells contributes to the observed racial differences in PCa progression. High expression levels of ERVs and ISGs correlate with favorable disease outcome in several solid tumors, making this anti-viral pathway a potential target for an activation therapy. Anti-viral immune response pathways can be activated using the nucleotide analog 5AzaC, a methyltransferase inhibitor, which has been used to treat solid tumors including breast, ovarian and colorectal cancer. We have developed a unique resource of tumor-adjacent cancer-associated fibroblasts (CAFs) from 25 AA and 25 EA patients, which allows us, for the first time, to experimentally test antiviral immune response pathways in different races. In Aim 1 we will investigate whether 5AzaC and/or type 1 IFN enhance the activity of ISGs in CAFs of AA and EA. We will also characterize the differential effect of AA and EA CAFs on the development and growth of prostate tumor cells and the effect of 5AzaC and/or IFN treatment on the stromal phenotype when exposed to tumor cells. In Aim 2 we will explore whether DCs co-cultured with AA CAFs and EA CAFs display differences in IFN production and T-cell activation. In Aim 3 we will investigate protein markers for ERVs, IFNs, ISGs, and activated DCs by immunohistochemistry of tumor samples. We will determine whether expression differences in these markers can result in a prognosticator of outcome and efficacy for PCa treatment. For this aim, we will employ 80 AA and 80 EA cases embedded in FFPE, hundreds of cases preserved as Tissue MicroArrays (TMAs), and 13 pairs of AA and EA cystoprostatectomies (controls). Overall, our studies will impact PCa management of AA patients, including strengthening of criteria for enrollment in active surveillance and initiation of possible new therapies.

项目总结/摘要非洲裔美国人（AA）比欧洲裔美国人总体上更晚期前列腺癌（PCa）（EA）。即使社会经济因素得到控制，AA的预后也比EA差。癌症的阶段。此外，35%的AA患者被分配到积极监测，而不是根治性治疗，最终不得不接受治疗，由于疾病进展，相比之下，只有15%的EA患者。在初步研究中，我们观察到，与AA相比，EA PCa患者的肿瘤相邻间质。这条途径始于激活内源性逆转录病毒，其在人类基因组中普遍存在，但通常是DNA甲基化的，不活跃。在EA前列腺癌间质中，ERVs被激活，具有较高的表达和较低的DNA甲基化在AA。当被激活时，ERV产生dsRNA，其反过来激活1型干扰素（IFN），其是在EA中也高于AA前列腺癌基质。干扰素然后激活干扰素刺激的基因（ISG），这是更高的表达在EA，而不是AA基质。最后，我们看到更高的表达 EA中活化的树突状细胞（DC）的标志物水平，而AA基质中没有。DC是免疫系统细胞，是IFN的最终靶点，可以抗肿瘤。我们假设抗病毒的表观遗传控制前列腺基质细胞中的免疫应答途径有助于观察到的PCa的种族差异进展ERV和ISG的高表达水平与几种实体瘤的良好疾病结局相关。肿瘤，使这种抗病毒途径成为激活疗法的潜在靶点。抗病毒免疫应答可以使用核苷酸类似物5AzaC（一种甲基转移酶抑制剂）激活通路，用于治疗实体瘤，包括乳腺癌、卵巢癌和结肠直肠癌。我们开发了一种独特的资源来自25名AA和25名EA患者的肿瘤相邻癌症相关成纤维细胞（CAF），这使我们能够第一次在不同种族中实验性地测试抗病毒免疫反应途径。在目标1中，研究5AzaC和/或1型IFN是否增强AA和EA的CAF中ISGs的活性。我们还将表征AA和EA CAF对前列腺肿瘤细胞的发育和生长的不同作用以及当暴露于肿瘤细胞时，5AzaC和/或IFN处理对基质表型的影响。在目标2中我们将探索与AA CAFs和EA CAFs共培养的DC是否显示IFN产生的差异， T细胞活化在目标3中，我们将通过以下方法研究ERV、IFN、ISG和活化的DC的蛋白标记物：肿瘤样品的免疫组织化学。我们将确定这些标记物的表达差异是否可导致PCa治疗的结果和功效的预测器。为此，我们将雇用80名AA， 80例EA病例包埋在FFPE中，数百例保存为组织微阵列（TMAs），13对 AA和EA膀胱切除术（对照）。总体而言，我们的研究将影响AA患者的PCa管理，包括加强积极监测的入选标准和启动可能的新疗法。