Treg functional changes: a novel immune regulatory effect underlying the benefit of statin drug use on lethal prostate cancer

项目摘要 先前的研究表明，他汀类药物的使用和风险之间一直存在很强的负相关性， 发展致命的前列腺癌，和一个更强的保护作用与更长的使用时间。进一步 对于临床局限性前列腺癌的男性，他汀类药物与进展至 转移和死于前列腺癌。他汀类药物作为化学预防和 治疗（佐剂）剂，他汀类药物相互作用的机制的额外表征 需要肿瘤微环境。Yes相关蛋白（雅普）是一种转录调控因子， 在调节性T淋巴细胞（Tlymphocyte，Tlymphocyte）中表达。他汀类药物已被证明可以抑制雅普核 Foxp 3介导的Treg免疫抑制功能所需的易位（通过雅普磷酸化）。因此，在本发明中， 我们建议研究他汀类药物和YAP介导的Treg功能障碍之间的关系，这是一种新的治疗方法。 他汀类药物可能通过免疫调节机制阻止致死性 前列腺癌在以下具体目标。对于Aim 1（K99阶段），我们将创建一个新的组织微阵列 一组包括临床病理学匹配的前列腺切除术时他汀类药物使用者和非使用者 特色我们将评估TcP与磷酸化雅普的比例是否与TcP的细胞质中TcP的比例有关。 他汀类药物使用者和非使用者的前列腺免疫细胞特征不同， 用户和非用户。对于目标2（R 00阶段），我们将进行一项原则验证随机试验， 他汀类药物对诊断为前列腺癌的男性中YAP介导的Treg功能障碍的影响， 接受子宫切除术。这项原理验证试验还将提供一个受控环境，以评估 单一类型他汀类药物和给药方案克服他汀类药物类型异质性的作用， 目的1中的观察性研究中的剂量。潜在偏倚，如适应症混杂，将被 通过使用随机化来最小化。我们将利用生物学方面的大量专业知识， 前列腺癌组织中存在的免疫细胞谱的测量和我们建立的， 在JHU用相关存档组织表征前列腺癌队列。这个的翻译价值 工作在于表征他汀类药物对新的免疫调节机制的作用的能力， 这可能与前列腺癌的免疫治疗有关。这项研究计划是 辅之以基于申请人癌症流行病学背景的培训计划， 研究综合方法，包括以下方面的新培训：1）提供流行病学观点， 多学科团队科学合作; 2）进行组织生物标志物验证研究; 3）临床 试验设计和实施。合并的研究和培训计划将为申请人做好准备， 成功的独立研究生涯集中在将癌症生物标志物转化为改善的人群 健康成果。

PROJECT SUMMARY Prior research has demonstrated a consistently strong inverse association between statin drug use and risk of developing lethal prostate cancer, and a stronger protective effect with a longer duration of use. Further, in men with clinically localized prostate cancer, statins are associated with a reduced risk of progression to metastasis and dying from prostate cancer. For statins to have clinical utility as chemopreventive and therapeutic (adjuvant) agents, additional characterization of the mechanisms through which statins interact with the tumor microenvironment is needed. Yes-associated protein (YAP) is a transcriptional regulator highly expressed in regulatory T lymphocytes (Tregs). Statin drugs have been shown to inhibit YAP nuclear translocation (via YAP phosphorylation) required for Foxp3-meditated Treg immunosuppressive function. Thus, we propose to investigate the association between statin drugs and YAP-mediated Treg dysfunction, a novel immune-modulatory mechanism through which statins may impede development and progression of lethal prostate cancer in the following specific aims. For Aim 1 (K99 phase) we will create a new tissue microarray set including statin users and nonusers at the time of prostatectomy matched on clinical pathological characteristics. We will evaluate whether the proportion of Tregs with phosphorylated YAP in the cytoplasm of Tregs differs between statin users and nonusers, and if the prostate immune cell profile differs among statin users and nonusers. For Aim 2 (R00 phase), we will conduct a proof-of-principle randomized trial investigating the effect of statins on YAP-mediated Treg dysfunction in men diagnosed with prostate cancer scheduled to receive prostatectomy. This proof-of-principle trial will also provide a controlled environment to assess the effect of a single type of statin and dosing schedule to overcome heterogeneity in the type of statin drugs and dose in the observational study purposed in Aim 1. Potential biases, such as confounding by indication, will be minimized through the use of randomization. We will leverage the tremendous expertise in the biology and measurement of the immune cell profile present in prostate cancer tissue and our established, well characterized prostate cancer cohorts with associated archived tissue at JHU. The translational value of this work lies in the ability to characterize the effect of statin drugs on a novel immunemodulatory mechanism, which may be relevant in the setting of immune-based therapy for prostate cancer. This research plan is complemented by a training plan that builds on the applicant’s background in cancer epidemiology and research synthesis methods and includes new training in 1) contributing an epidemiologic perspective in multidisciplinary team science collaborations; 2) conducting tissue-biomarker validation studies; and 3) clinical trial design and implementation. The combined research and training plans will prepare the applicant for a successful independent research career focused the translation of cancer biomarkers into improved population health outcomes.