Modulation of antitumor immunity by dietary soy and its isoflavone constituents

描述（由申请人提供）：大豆及其衍生食品是促进健康的生物活性植物化学物质的丰富来源。大豆异黄酮被假设通过多种途径影响前列腺癌（PCa）的进展；然而，有一个领域很少受到关注，那就是大豆成分对免疫系统的影响。随着免疫治疗前列腺癌（如Provenge）的不断发展和批准，以及最近对免疫系统在调节前列腺癌发展中的作用的认识，这一点非常重要。最佳抗肿瘤免疫反应的一个障碍是免疫抑制性髓源性抑制细胞（MDSC）。MDSC通过多种系统机制和肿瘤微环境发挥作用。我们的研究小组和其他研究人员已经表明，MDSC是实体瘤患者总生存率降低的相关生物标志物，早期报告表明，MDSC在PCa患者中升高。我们的初步数据表明，膳食大豆可调节小鼠T细胞增殖和细胞对促炎细胞因子的反应。此外，基因素促进外周血单核细胞向中性粒细胞的体外分化，抑制MDSC的体外生成。我们开发了一种富含异黄酮的新型大豆面包。这种面包是安全的，并且在经历生化失败的前列腺癌患者中具有良好的依从性。与基线相比，接受大豆面包干预的患者血液中的MDSC和促炎性细胞因子显著降低。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估。我们对膳食大豆及其异黄酮成分如何调节与炎症和前列腺癌相关的信号转导途径和免疫细胞群感兴趣。我们假设膳食大豆可能通过抑制免疫抑制细胞的扩张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物在体外促炎刺激后如何调节骨髓细胞的分化和免疫抑制功能。我们还将在PCa的TRAMP和Hi-myc模型中评估饮食系统对MDSC扩张和功能的影响，以及淋巴细胞对相关免疫刺激的体外反应。一项I期临床试验将在诊断为前列腺癌的男性中进行，并随机分配在前列腺切除术前4周接受大豆面包（实验组）或小麦面包（对照组）的饮食干预，以评估基线和干预后外周血中的促炎细胞因子、免疫细胞标志物（如MDSC、T细胞、NK细胞）和T细胞增殖。这些研究将为膳食大豆及其异黄酮成分如何调节与前列腺癌发生和进展相关的免疫方面提供全面的翻译理解。

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.