Disrupting the Prostate Tumor Microenvironment in African American Men to Promote Response to Immuno-Modulatory Therapy

项目摘要 已知非洲裔美国人（AAM）患有更晚期的疾病， 和社会经济因素。具体到生物因素，有新的数据表明，AAM与 前列腺癌（PCa）具有免疫抑制性肿瘤免疫微环境（TIME），其特征在于 低DNA损伤修复和高IFN-应答途径。因此，免疫介质和DNA损伤 反应可能在AAM中的PCa生物学中起主要作用。的机制和潜在的治疗效果 结合免疫调节剂来破坏AAM与PCa的治疗增益的时间是一个活跃的领域， 调查此外，免疫调节治疗是否对免疫细胞类型有不同的影响， 在AAM与欧洲-美国男性（EAM）的时间内，目前尚不清楚。本研究中提出的研究 应用程序将首先计算解卷积AAM和EAM的时间，突出功能 关键免疫细胞和可溶性免疫介质的特性。为了克服细胞系模型的局限性， 我们将使用一种新的生物工程平台来研究肿瘤-免疫相互作用，并从机制上确定如何 STING-IFN应答途径的差异影响对免疫调节剂的应答和/或抗性。 接下来，我们将评估AAM和EAM的时间差异如何影响对以下治疗反应： 使用患者来源的外植体的免疫调节剂-来自新鲜活手术的独特离体模型 标本重要的是，我们还将在一系列患者来源的活检和血液样本中验证这些结果 作为ADT、RT和免疫疗法相结合的II期临床研究的一部分， （NCT03543189）。这些研究将揭示可用于确定新治疗方法的机制 改善AAM伴PCa患者结局的方法。

PROJECT SUMMARY African-American men (AAM) are known to present with more advanced disease resulting from both biological and socio-economic factors. Specific to biological factors, there is emerging data suggesting that AAM with prostate cancer (PCa) have an immunosuppressive tumor immune microenvironment (TIME) characterized by low DNA damage repair and high IFN-response pathway. Consequently, immune mediators and DNA damage response may play a major role in PCa biology in AAM. The mechanism and potential therapeutic benefit of combining immune modulators to disrupt the TIME for therapeutic gain in AAM with PCa is an area of active investigation. Furthermore, whether immune-modulatory therapy has differential effects on immune cell-types within the TIME of AAM vs. European-American men (EAM) is currently unknown. The proposed studies in this application will first computationally deconvolute the TIME of AAM and EAM highlighting the functional characteristics of key immune cells and soluble immune mediators. To overcome the limitation of cell line models, we will use a novel bioengineered platform to study tumor-immune interactions and mechanistically define how differences in the STING-IFN response pathway impacts response and/or resistance to immune modulators. Next, we will evaluate how differences in the TIME from AAM and EAM may affect the therapeutic response to immune-modulators using patient-derived explants – a unique ex-vivo model from fresh viable surgical specimens. Importantly, we will also validate these results in serial patient-derived biopsies and blood samples that have been collected as part of a phase II clinical study combining ADT, RT and immunotherapy (NCT03543189). These studies will unravel mechanisms that can be exploited to identify new therapeutic approaches to improve outcomes in AAM with PCa.