Abstract 2585: Bioactive compounds or metabolites from black raspberries modulate T lymphocyte function, myeloid cell differentiation and Jak/STATsignaling
Authors: Mace Thomas A. , King Samantha , Ameen Zeenath , Elnaggar Omar , Young Gregory , Riedl Kenneth , Schwartz Steven , Clinton Steven , Knobloch Thomas , Weghorst Christopher , Lesinski Gregory B. 
Published: May 2015

Abstract
Bioactive phyotochemicals from natural products, such as black raspberries have direct anti-cancer properties on malignant cells in culture and in xenograft models. In addition, black raspberry components inhibit cancer progression in more complex rodent carcinogenesis models. Although mechanistic targets for black raspberry phytochemicals in cancer cells are beginning to emerge, the potential role in modulating host immune processes impacting cancer have not been systematically examined. We hypothesized that black raspberries contain compounds capable of eliciting potent immunomodulatory properties that impact cellular mediators relevant to chronic inflammation and tumor progression. In the present report, we studied both an ethanol extract from black raspberries (BRB-E) containing a diverse mixture of phytochemicals and two abundant phytochemical metabolites of black raspberries produced upon ingestion (Cyanidin-3-Rutinoside, C3R; Quercitin-3-rutinoside, Q3R). BRB-E inhibited proliferation of CD3/CD28 activated human CD4+ and CD8+ T lymphocytes. BRB-E also limited the viability of CD3+ T cells cultured in IL-2, and were potent inhibitors of IL-2-induced STAT5 phosphorylation. Conversely, BRB-E significantly enhanced the monokine-induced by gamma (MIG)-mediated chemotaxis of CD8+ T lymphocytes in transwell assays. This enhanced chemotaxis was associated with upregulated expression of CXCR3 on T lymphocytes. BRB-E also inhibited the in vitro expansion of myeloid-derived suppressor cells (MDSC). Consistent with the reduction in MDSC, pre-treatment of immune cells with BRB E attenuated IL-6-mediated signal transducer and activator of transcription-3 (STAT3) phosphorylation. Finally, the C3R and Q3R metabolites were also found to be immunomodulatory, as C3R inhibited proliferation of CD3/CD28 activated T lymphocytes and STAT5 phosphorylation, while Q3R inhibited MDSC expansion and STAT3 signaling but not STAT5. Together these data indicate that black raspberries or their physiologically-relevant metabolites contain phytochemicals that affect immune processes relevant to carcinogenesis. Furthermore, specific components and their metabolites may be a source of lead compounds for drug development that exhibit targeted immunological outcomes or inhibition of specific STAT-regulated signaling pathways.
Citation Format: Thomas A. Mace, Samantha King, Zeenath Ameen, Omar Elnaggar, Gregory Young, Kenneth Riedl, Steven Schwartz, Steven Clinton, Thomas Knobloch, Christopher Weghorst, Gregory B. Lesinski. Bioactive compounds or metabolites from black raspberries modulate T lymphocyte function, myeloid cell differentiation and Jak/STATsignaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2585. doi:10.1158/1538-7445.AM2014-2585