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）：大豆及其从中衍生的食物是促进健康的丰富生物活性植物化学物质的来源。假设大豆异黄酮可以通过各种途径来影响前列腺癌（PCA）进展。但是，一个很少关注的领域是大豆成分对免疫系统的影响。这对于PCA的免疫疗法的持续开发和批准（Provenge）以及最近对免疫系统调节前列腺癌发展的欣赏是很重要的。最佳抗肿瘤免疫反应的一个障碍是免疫抑制髓样衍生的抑制细胞（MDSC）。 MDSC在系统和肿瘤微环境中通过多种机制起作用。我们的小组和其他人表明，MDSC是实体瘤患者的总体存活率降低相关的生物标志物，并且早期报告表明PCA患者的MDSC升高。我们的初步数据表明，饮食大豆调节小鼠中T细胞增殖和对促炎性细胞因子的细胞反应。此外，Genestein促进了外周血单核细胞的体外分化成嗜中性粒细胞，并抑制了体外MDSC的产生。我们开发了一种新型大豆面包，可提供高水平的异黄酮。这种面包是安全的，并且在患有生化衰竭的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的血液中MDSC和促炎性细胞因子的血液明显降低。这些数据表明，饮食大豆作为免疫调节剂的作用需要进一步的系统评估。我们对饮食大豆及其异黄酮成分如何调节信号转导途径和与炎症和前列腺癌相关的免疫细胞种群感兴趣。我们假设饮食大豆可以通过抑制免疫抑制细胞的扩展并减少对促炎性信号的细胞反应来防止PCA进展。我们将确定大豆异黄酮或它们的代谢产物如何通过促炎性刺激在体外刺激后调节髓样细胞的分化和免疫抑制功能。我们还将评估饮食SY对PCA的流浪汉和HI-MYC模型中MDSC扩展和功能的影响，以及淋巴细胞对相关免疫刺激的离体反应。 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.这些研究将对饮食中的大豆及其异黄酮成分如何调节与前列腺癌发展和进展相关的免疫方面进行全面的转化理解。