Intensive cholesterol-lowering intervention and anti-tumor immunity modeled in prostate cancer

项目摘要 在流行病学研究中，他汀类药物与降胆固醇治疗之间有很强的相关性 以及降低前列腺癌死亡风险。动物研究表明，降低胆固醇可以减少 前列腺癌的发展降低前列腺癌患者胆固醇的生物效应是 没有完全理解。很可能降低胆固醇可以直接抑制肿瘤的生长， 转移的可能性然而，我们的初步数据表明另一个重要的机制：胆固醇- 降低可增强抗肿瘤免疫应答。在我们的动物模型中， 通过免疫细胞中的mTOR通路进行信号传导。我们发现，同样的信号变化也出现在 前列腺癌患者的血液胆固醇降低。我们的初步数据还表明， 降低胆固醇可增强对长期癌症控制至关重要的免疫记忆细胞。我们的工作 假设降低血清胆固醇（1）会降低淋巴细胞中的TORC 2信号传导， 中枢记忆性CD 8 + T细胞的形成，（2）可以通过控制TcB来优化，以及（3）直接增加 肿瘤免疫原性为了验证这一假设，并与我们的小鼠模型的发现相关，我们提出了平行 小鼠和人类临床研究。因此，目的1评价了降低胆固醇对CD 8 + T细胞的影响。 记忆细胞以及适应性免疫应答的其他关键成分，如调节性T细胞。 我们的初步数据表明，降低胆固醇使肿瘤更“可见”的免疫系统， 增加热休克蛋白的表达。我们评估降低胆固醇对肿瘤的影响 这可能会改变免疫反应。我们还评估了肿瘤的影响，暴露在胆固醇中- 降低树突状细胞、巨噬细胞和中性粒细胞。目的2在一项前瞻性研究中评价胆固醇降低 在低风险和中等风险前列腺癌男性中进行的临床试验，通过积极监测进行管理。这些 男性癌症进展的风险很高，需要根治性手术或放射治疗，这往往使男性 患有永久性尿失禁和勃起功能障碍在拟议的试验中，新诊断的前列腺患者 癌症将经历最大的胆固醇降低或标准处理。前列腺活检组织 并在开始治疗后进行比较，以确定胆固醇降低是否增加了CD 8 + T细胞。 肿瘤，这是抗肿瘤免疫反应所需的。我们还将检查血液中的免疫细胞 以识别和丰富最有可能应答的患者亚组。一项积极的研究将提供有力的理由 一项3期多中心临床试验，以确定降低胆固醇是否可以防止形成或 前列腺癌的发展它还将提供一种免疫机制，可以潜在地改善结果 前列腺癌以外的其他癌症。

PROJECT SUMMARY In epidemiologic studies, a strong association has been noted between cholesterol-lowering therapy with statins and lower risk of death from prostate cancer. Animal studies suggest that cholesterol-lowering can decrease the progression of prostate cancer. The biologic effects of lowering-cholesterol in prostate cancer patients are not fully understood. It is very likely that lowering cholesterol can directly inhibit the growth of the tumor and its potential to metastasize. However, our preliminary data suggest another important mechanism: cholesterol- lowering enhances an antitumor immune response. In our animal models, cholesterol-lowering reduced signaling through the mTOR pathway in immune cells. We show that this same signaling change is seen in prostate cancer patients when their blood cholesterol is lowered. Our preliminary data also suggest that cholesterol-lowering enhances immune memory cells that are critical for long-term cancer control. Our working hypothesis is that lowering serum cholesterol (1) decreases TORC2 signaling in lymphocytes and enhances formation of central memory CD8+ T cell, (2) can be optimized by controlling Tregs, and (3) directly increases tumor immunogenicity. To test this hypothesis and to relate findings from our mouse models, we propose parallel mouse and human clinical studies. Therefore, Aim 1 evaluates the effects of cholesterol-lowering on CD8+ memory cells as well as other critical components of the adaptive immune response, such as regulatory T cells. Our preliminary data show that cholesterol-lowering makes the tumor more “visible” to the immune system by increasing the expression of heat shock proteins. We evaluate the effects of cholesterol-lowering on the tumor itself, which may then alter the immune response. We also assess the effects of tumor, exposed to cholesterol- lowering, on dendritic cells, macrophages and neutrophils. Aim 2 evaluates cholesterol-lowering in a prospective clinical trial in men with low and intermediate-risk prostate cancer being managed with active surveillance. These men are at high risk for cancer progression and needing radical surgery or radiation, which often leaves men with permanent incontinence and erectile dysfunction. In the proposed trial, men with newly diagnosed prostate cancer will undergo maximal cholesterol-lowering or standard management. The prostate biopsy tissue before and after starting treatment will be compared to determine if cholesterol lowering increases CD8+ T cells in the tumor, which are required for an antitumor immune response. We will also examine immune cells in the blood to identify and enrich for patient subgroups most likely to respond. A positive study will provide a strong rationale for a phase 3, multicenter clinical trial to determine if cholesterol-lowering can prevent the formation or progression of prostate cancer. It will also provide an immune mechanism that can potentially improve outcomes in other cancers beyond prostate cancer.