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

项目总结 先前的研究表明，他汀类药物的使用与糖尿病风险之间一直存在着强烈的负相关 罹患致命性前列腺癌，使用时间越长，保护作用越强。此外，在 临床上患有局限性前列腺癌的男性，他汀类药物与进展到 转移和死于前列腺癌。他汀类药物作为化学预防和治疗的临床用途 治疗(佐剂)药物，他汀类药物相互作用机制的额外表征 需要肿瘤的微环境。YAP是一种高度转录调控蛋白。 表达于调节性T淋巴细胞(Tregs)。他汀类药物已被证明可以抑制YAP核 Foxp3介导的Treg免疫抑制功能所需的易位(通过YAP磷酸化)。因此， 我们建议调查他汀类药物和YAP介导的Treg功能障碍之间的联系，这是一种新的 他汀类药物抑制致死性白血病发生发展的免疫调节机制 前列腺癌的具体目标有以下几点。对于目标1(K99阶段)，我们将创建一个新的组织微阵列 SET包括在前列腺摘除时使用他汀类药物和不使用他汀类药物与临床病理相匹配 特点。我们将评估Tregs与磷酸化的YAP在细胞质中的比例是否 他汀类药物使用者和非他汀类药物使用者之间的Tregs不同，如果他汀类药物之间的前列腺免疫细胞图谱不同 用户和非用户。对于目标2(R00阶段)，我们将进行原则证明随机试验研究 他汀类药物对前列腺癌患者YAP介导的Treg功能障碍的影响 接受前列腺切除术。这项原则证明试验还将提供一个受控环境，以评估 单一类型的他汀类药物和给药方案对克服他汀类药物和 目标1中规定的观察性研究中的剂量。潜在的偏差，如指征混淆，将是 通过使用随机化将其最小化。我们将利用生物学领域的巨大专业知识， 前列腺癌组织和我们已建立的很好的免疫细胞图谱的测量 描述了JHU的前列腺癌队列和相关的存档组织。这个词的翻译价值 工作在于能够表征他汀类药物对一种新的免疫调节机制的影响， 这可能与前列腺癌的免疫治疗相关。这项研究计划是 辅以以申请人癌症流行病学背景为基础的培训计划，以及 研究综合方法，并包括1)提供流行病学观点方面的新培训 多学科团队科学合作；2)进行组织生物标记物验证研究；3)临床 试行设计和实施。综合研究和培训计划将使申请者做好准备 成功的独立研究生涯专注于将癌症生物标记物转化为改善的人群 健康结果。

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.