Modulation of antitumor immunity by dietary soy and its isoflavone constituents

食用大豆及其异黄酮成分调节抗肿瘤免疫力

基本信息

批准号：
8695304
负责人：
Gregory B. Lesinski
金额：
$ 30.98万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-03 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8695304
关键词：
Adenocarcinoma Agonist Area Attention Biochemical Biological Biological Markers Blood Bread Cancer Patient Cell Cycle Cells Cellular biology Clinical Research Data Development Diagnosis Diet Dietary Intervention Etiology Evaluation Experimental Neoplasms Failure Food Foundations Future Generations Genistein Health Hormones Human Immune Immune response Immune system Immunity Immunologic Monitoring Immunomodulators Immunosuppressive Agents Immunotherapy In Vitro Indolent Inflammation Inflammatory Interleukin-10 Interleukin-6 Intervention Isoflavones Lymphocyte Malignant Neoplasms Malignant neoplasm of prostate Metabolism Modeling Mus Myelogenous Myeloid Cells Natural Killer Cells Operative Surgical Procedures Pathway interactions Patients Peripheral Blood Mononuclear Cell Phase I Clinical Trials Phenotype Phytochemical Play Population Prevention strategy Process Property Prostate Prostate Cancer therapy Prostatectomy Randomized Regimen Reporting Research Role Signal Transduction Signal Transduction Pathway Solid Solid Neoplasm Source Soybeans Staging Stimulus Structure of base of prostate Suppressor-Effector T-Lymphocytes T-Cell Proliferation T-Lymphocyte Testing Tissues Transforming Growth Factors Transgenic Organisms Wheat Work antiangiogenesis therapy arm base bone health cancer prevention cancer risk carcinogenesis cytokine cytotoxic daidzein experience feeding immune function improved in vivo Model insight interest meetings men neutrophil novel peripheral blood phase 2 study preclinical study prevent prostate cancer model public health relevance response soy soy protein isolate translational study tumor tumor microenvironment tumor progression

项目摘要

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.

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。据推测，大豆异黄酮可通过多种途径影响前列腺癌 (PCa) 的进展；然而，很少有人关注的一个领域是大豆成分对免疫系统的影响。这对于 PCa 免疫疗法（例如 Provenge）的持续开发和批准以及最近对免疫系统调节前列腺癌发展的认识非常重要。最佳抗肿瘤免疫反应的障碍之一是免疫抑制性骨髓源性抑制细胞 (MDSC)。 MDSC 通过多种机制在全身和肿瘤微环境中发挥作用。我们的团队和其他人已经表明，MDSC 是与实体瘤患者总生存率降低相关的相关生物标志物，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，基因斯坦促进外周血单核细胞体外分化为中性粒细胞并抑制体外MDSC生成。我们开发了一种新型大豆面包，可提供高含量的异黄酮。这种面包是安全的，并且患有生化衰竭的 PCa 男性患者的依从性良好。与基线相比，接受大豆面包干预的患者血液中的 MDSC 和促炎细胞因子显着降低。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。我们感兴趣的是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。我们推测，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。我们还将评估膳食sy对PCa 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。 I 期临床试验将在诊断患有 PCa 的男性中进行，并在前列腺切除术前随机接受大豆面包（实验组）或小麦面包（对照组）饮食干预 4 周，以评估促炎细胞因子、免疫细胞标记物（例如，基线和干预后以及新鲜分离的前列腺组织中的 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、转化性的理解。