Modulation of antitumor immunity by dietary soy and its isoflavone constituents

描述（由申请人提供）：蚕豆和从它们中提取的食物是促进健康的生物活性植物化学物质的丰富来源。大豆黄酮被假设通过各种途径影响前列腺癌（PCa）的进展;然而，一个很少受到关注的领域是大豆成分对免疫系统的影响。这对于持续开发和批准用于PCa的基于免疫的疗法（例如; Provenge）和最近对免疫系统调节前列腺癌发展的认识。最佳抗肿瘤免疫应答的一个障碍是免疫抑制性髓源性抑制细胞（MDSC）。MDSC通过多种机制在全身和肿瘤微环境中发挥作用。我们的小组和其他人已经表明，MDSC是一个相关的生物标志物，与实体瘤患者的总生存率降低，早期的报告表明，MDSC在PCa患者中升高。我们的初步数据表明，饮食大豆调节小鼠T细胞增殖和细胞对促炎细胞因子的反应。此外，genestein促进外周血单核细胞在体外分化为中性粒细胞，并抑制体外MDSC的产生。我们开发了一种新的大豆面包，它提供了高水平的大豆酮。这种面包是安全的，在经历生化失败的PCa男性中符合良好的依从性。与基线相比，接受大豆面包干预的患者血液中的MDSC和促炎细胞因子显著降低。这些数据表明，膳食大豆作为免疫调节剂的作用需要进一步的系统评价。我们感兴趣的是饮食大豆和它的主要成分如何调节信号转导途径和免疫细胞群相关的炎症和前列腺癌。我们推测，饮食中的大豆可能通过抑制免疫抑制细胞的扩增和减少细胞对促炎信号的反应来预防前列腺癌的进展。 我们将确定大豆异黄酮或其代谢产物如何调节体外促炎刺激后骨髓细胞的分化和免疫抑制功能。我们还将评估饮食sy对PCa的TRAMP和Hi-myc模型中MDSC扩增和功能的影响以及淋巴细胞对相关免疫刺激的离体反应。将在被诊断患有PCa并且在前列腺切除术之前随机接受大豆面包（实验组）或小麦面包（对照组）的饮食干预4周的男性中进行I期临床试验，以评估基线和干预后外周血和新鲜分离的前列腺组织中的促炎细胞因子、免疫细胞标志物（例如MDSC、T细胞、NK细胞）和T细胞增殖。这些研究将提供一个全面的，翻译的理解，如何饮食大豆和它的大豆成分调节免疫方面相关的前列腺癌的发展和进展。

DESCRIPTION (provided by applicant): Soybeans and the foods derived from them are a rich source of bioactive phytochemicals that promote health. Soy isoflavones are hypothesized to act through various pathways to impact prostate cancer (PCa) progression; however, one area that has received very little focus is the impact of soy components on the immune system. This is of importance with the ongoing development and approval of immune-based therapies for PCa (e.g.; Provenge) and a recent appreciation for the immune system in regulating prostate cancer development. One barrier to optimal anti-tumor immune responses are immunosuppressive myeloid-derived suppressor cells (MDSC). MDSC act through a variety of mechanisms systemically and in the tumor microenvironment. Our group and others have shown that MDSC are a relevant biomarker associated with reduced overall survival in patients with solid tumors and early reports indicate MDSC are elevated in PCa patients. Our preliminary data demonstrate that dietary soy modulates T cell proliferation and the cellular response to pro-inflammatory cytokines in mice. Further, genestein promoted in vitro differentiation of peripheral blood mononuclear cells into neutrophils and inhibited in vitro MDSC generation. We developed a novel soy bread which delivers high levels of isoflavones. This bread was safe and met with favorable compliance in men with PCa experiencing biochemical failure. Compared to baseline, MDSC and pro- inflammatory cytokines were significantly lower in the blood of patients receiving soy bread intervention. These data suggest that the role of dietary soy as an immunomodulator requires further systematic evaluation. We are interested in how dietary soy and its isoflavone constituents modulate signal transduction pathways and immune cell populations relevant to inflammation and prostate cancer. We hypothesize that dietary soy may prevent PCa progression by inhibiting expansion of immunosuppressive cells and reducing the cellular response to pro-inflammatory signals. We will determine how soy isoflavones or their metabolites modulate the differentiation and immunosuppressive function of myeloid cells after in vitro stimulation with pro- inflammatory stimuli. We will also evaluate the effects of dietary sy on MDSC expansion and function in the TRAMP and Hi-myc models of PCa and the ex vivo response of lymphocytes to relevant immune stimuli. A phase I clinical trial will be conducted in men diagnosed with PCa and randomized to receive dietary intervention with soy bread (experimental arm) or wheat bread (control arm) for 4 weeks prior to prostatectomy to evaluate pro-inflammatory cytokines, immune cell markers (e.g. MDSC, T cells, NK cells) and T cell proliferation in peripheral blood at baseline and following intervention and freshly isolated prostate tissue. These studies will provide a comprehensive, translational understanding of how dietary soy and its isoflavone components modulate aspects of immunity relevant to prostate cancer development and progression.