Modulation of antitumor immunity by dietary soy and its isoflavone constituents

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.