Abstract 4278: Soy isoflavones and their metabolites modulate IL-12-induced NK cell IFN-γ production
Authors: Mace Thomas A. , King Samantha , Farren Matthew , McMichael Elizabeth , Scoville Steven , Carson William E. , Young Gregory , Thomas-Ahner Jennifer , Riedl Kenneth M. , Schwartz Steven , Clinton Steven K. , Lesinski Gregory 
Published: August 2015

Abstract
Soybeans and foods derived from them are a rich source of phytochemcials that have gained attention due to their ability to affect obesity, metabolism, cancer, and inflammation. Soy isoflavones (genistein and daidzein) have also been shown to be differentially metabolized between individuals. This is presumably due to differences in gut microbiota, and can lead to production of terminal isoflavone metabolites such as O-desmethylangolensin (ODMA) and equol. In a prior phase-I clinical study conducted by our group, patients with prostate cancer received a novel soy-enriched bread product. Analysis of blood and urine following soy intervention revealed that men clustered into distinct groups based on their ability to metabolize daidizein into either ODMA or equol. Reduced pro-inflammatory cytokines and percentages of Tregs and MDSC were also observed in the blood of patients after 8 weeks of soy bread intervention as compared to baseline. Given these differences, we hypothesized that individual isoflavones and metabolites would have unique immunomodulatory effects upon human natural killer (NK) cell function. Although a limited number of prior studies have evaluated how soy isoflavones or their metabolites modulate inflammation and different immune subsets (monocytes, macrophages, DCs), their role in NK cell biology remains poorly defined. Understanding the role of soy isoflavones and their metabolites in regulating NK cell activity is critical due to NK cells’ importance in the anti-tumor response and immunosurveillance. We found that the soy isoflavones and their metabolites did not affect the viability of healthy donor PBMC (n = 3) at concentrations as high as 25μM. However, pre-treatment of healthy donor PBMC (n = 3) with genistein (mean 7.1 ng/ml ±1.3) or equol (mean 6.7 ng/ml ±1.8) for 4 hours and then stimulated with IL-12/18 for 72 hours decreased IFN-γ production compared to unstimulated controls (mean 26.7 ng/ml ±16.1). In contrast, daidzein and ODMA had no effect. We next utilized intracellular flow cytometry to determine the cellular subset(s) that were modulated by soy isoflavones or their metabolites. These data revealed that only genistein and equol decreased the percentage of IL-12/18 induced IFN-γ producing NK cells (CD56+CD3-) by 30% and 53%, respectively. There was no observed difference in other IFN-γ producing immune subsets (T and NKT cells) when cultured with the soy isoflavones or metabolites. Furthermore, we found soy isoflavones and metabolites altered in vitro cytotoxicity of human IL-12 stimulated NK cells. Ongoing studies in our laboratory are elucidating the precise signaling pathways downstream of IL-12 in human NK cells that are modulated in response to soy isoflavones and their bioactive metabolites. This study provides critical insight regarding the impact of dietary soy on NK cell mediated responses potentially informing the use of soy during chemopreventive or immune based therapies.
Citation Format: Thomas A. Mace, Samantha King, Matthew Farren, Elizabeth McMichael, Steven Scoville, William E. Carson, Gregory Young, Jennifer Thomas-Ahner, Kenneth M. Riedl, Steven Schwartz, Steven K. Clinton, Gregory Lesinski. Soy isoflavones and their metabolites modulate IL-12-induced NK cell IFN-γ production. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4278. doi:10.1158/1538-7445.AM2015-4278