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

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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.