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

Treg 功能变化：一种新的免疫调节作用，是他汀类药物对致命性前列腺癌有益的基础

• 批准号: 10554641
• 负责人: Michael Thomas Marrone
• 金额: $ 24.9万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-09 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554641
• 关键词: Adjuvant; Area; Biological; Biology; CD8B1 gene; Cancer Control; Cell physiology; Cells; Cessation of life; Characteristics; Chemopreventive Agent; Clinical; Clinical Trials Design; Collaborations; Complement; Controlled Environment; Cytoplasm; Development; Diagnosis; Disease; Disease Progression; Dose; Drug usage; Epidemiologic Methods; Epidemiologist; Epidemiology; FOXP3 gene; Foundations; Functional disorder; Genetic Transcription; Goals; Health; Helper-Inducer T-Lymphocyte; Heterogeneity; Immune; Immune response; Immunosuppression; Immunotherapy; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Mediating; Medical Oncology; Mentors; Methods; Molecular; Nature; Neoplasm Metastasis; Nuclear Protein; Nuclear Translocation; Observational Study; Operative Surgical Procedures; Outcome; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Phosphorylation; Placebos; Play; Prostate; Prostate Cancer therapy; Prostatectomy; Prostatic Neoplasms; Proteins; Randomized; Regulatory T-Lymphocyte; Research; Research Project Grants; Research Training; Risk; Role; Sampling; Schedule; Science; T cell response; Testing; Therapeutic; Time; Tissue Microarray; Tissues; Training; Training Programs; Translations; Tumor Antigens; Uncertainty; Work; advanced prostate cancer; anti-tumor immune response; base; biomarker validation; cancer biomarkers; cancer clinical trial; cancer epidemiology; career; cohort; density; epidemiology study; evidence base; experience; improved; men; multidisciplinary; novel; pleiotropism; population based; population health; prostate cancer progression; protective effect; randomized trial; response; tissue archive; tissue biomarkers; tumor; tumor microenvironment; validation studies

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.

项目摘要 先前的研究表明，他汀类药物使用与风险之间始终存在较强的反相关性 发展致命的前列腺癌，并具有更强的使用持续时间的保护作用。此外，在 患有临床局部前列腺癌的男性，他汀类药物与进展的风险降低有关 转移和死于前列腺癌。他汀类药物的临床实用性为化学预防和 治疗（辅助）剂，汀类药物与之相互作用的机制的其他表征 需要肿瘤微环境。是相关蛋白（YAP）是转录调节剂高度 在调节性T淋巴细胞（Tregs）中表达。他汀类药物已被证明可以抑制YAP核 FOXP3鉴定的Treg免疫抑制功能所需的易位（通过YAP磷酸化）。那， 我们建议研究他汀类药物与YAP介导的Treg功能障碍之间的关联，这是一种新型 他汀类药物可能阻碍致命的发育和进展的免疫调节机制 前列腺癌在以下特定目的中。对于AIM 1（K99阶段），我们将创建一个新的组织微阵列 在前列腺切除术时，包括他汀类药物的使用者和非使用者在临床病理上匹配 特征。我们将评估在细胞质中具有磷酸化YAP的Treg的比例 Tregs在他汀类药物用户和非使用者之间有所不同，如果汀类药物的前列腺免疫细胞谱差异 用户和非使用者。对于AIM 2（R00阶段），我们将进行原则证明的随机试验调查 他汀类药物对被诊断为前列腺癌的男性YAP介导的Treg功能障碍的影响 接受前列腺切除术。本原则试验还将提供一个受控的环境来评估 汀类药物和给药时间表的影响，以克服他汀类药物的异质性和 在目的1中的观察性研究中的剂量。潜在的偏见，例如通过指示混淆，将是 通过使用随机化来最小化。我们将利用生物学的巨大专家 测量前列腺癌组织中存在的免疫细胞谱和我们已建立的良好 表征了前列腺癌的队列与JHU相关的存档组织。这个的翻译价值 工作在于能够表征他汀类药物对新型免疫调节机制的影响的能力， 这可能与对前列腺癌的免疫治疗相关。该研究计划是 由培训计划完成，该计划以申请人的癌症流行病学背景为基础 研究合成方法，包括1）在1）贡献流行病学的观点 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 试用设计和实施。合并的研究和培训计划将为申请人做好准备 成功的独立研究职业集中于将癌症生物标志物转化为改善人群 健康结果。