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

项目摘要/摘要 非洲裔美国人(AA)总体上比欧洲裔美国人患有更晚期的前列腺癌(PCA) (EA)。即使控制了社会经济因素，AA的预后也比EA差。 癌症分期。此外，35%的再生障碍性贫血患者被分配到积极监测而不是激进治疗 最终由于疾病进展而不得不接受治疗，而电针患者的这一比例仅为15%。在……里面 初步研究，我们观察到整个抗病毒免疫反应途径在 电针前列腺癌患者与再生障碍性贫血患者的肿瘤邻近间质相比。这一途径始于激活 内源性逆转录病毒，普遍存在于人类基因组中，但通常是DNA甲基化和 处于非活动状态。在前列腺癌间质中，ERV被激活，高表达和低DNA甲基化 而不是在戒酒协会。当被激活时，ERV产生dsRNA，进而激活1型干扰素(IFN)，后者是 电针在前列腺癌间质中也高于AA前列腺癌间质。然后，干扰素激活干扰素刺激的表达 基因(ISGs)，在EA间质中表达更高，但在AA间质中表达不高。最后，我们看到了更高的表达 激活的树突状细胞(DC)标志物在EA间质中的水平，而不是AA间质。DC是一种免疫系统细胞， 是干扰素的终极靶点，可以抗肿瘤。我们假设抗病毒的表观遗传控制 前列腺间质细胞中的免疫反应通路对观察到的前列腺癌的种族差异有贡献 进步。ERV和ISGs的高表达水平与几种固体疾病的良好结局相关 肿瘤，使这一抗病毒途径成为激活疗法的潜在靶点。抗病毒免疫反应 通路可以用核苷酸类似物5AzaC激活，这是一种甲基转移酶抑制剂，它已经被 用于治疗实体肿瘤，包括乳腺癌、卵巢癌和结直肠癌。我们开发了一种独特的资源 来自25名AA和25名EA患者的癌旁肿瘤相关成纤维细胞(CAF)，这使得我们能够 第一次，对不同种族的抗病毒免疫反应途径进行实验测试。在目标1中，我们将 研究5AzaC和/或1型干扰素是否增强AA和EA CAF中ISGs的活性。我们还将 AA和EA CAF对前列腺癌细胞生长发育的不同影响 以及5AzaC和/或干扰素处理对肿瘤细胞间质表型的影响。在AIM 2 我们将探讨与AA CAF和EA CAF共培养的DC在干扰素产生和 T细胞被激活。在目标3中，我们将研究ERV、IFN、ISGs和激活的DC的蛋白质标记物 肿瘤标本的免疫组织化学。我们将确定这些标记的表达差异是否 可作为预测PCa治疗结果和疗效的指标。为此，我们将雇用80名机管局和 80例电针植入FFPE，数百例保存为组织微阵列(TMA)，13对 AA和EA膀胱前列腺切除术(对照组)。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登记标准和启动可能的新疗法。

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.