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Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling

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Abstract

Bioactive phytochemicals from natural products, such as black raspberries (BRB; Rubus occidentalis), have direct anticancer properties on malignant cells in culture and in xenograft models. BRB components inhibit cancer progression in more complex rodent carcinogenesis models. Although mechanistic targets for BRB 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 BRB contain compounds capable of eliciting potent immunomodulatory properties that impact cellular mediators relevant to chronic inflammation and tumor progression. We studied both an ethanol extract from black raspberries (BRB-E) containing a diverse mixture of phytochemicals and two abundant phytochemical metabolites of BRB produced upon ingestion (Cyanidin-3-Rutinoside, C3R; Quercitin-3-Rutinoside, Q3R). BRB-E inhibited proliferation, and viability of CD3/CD28 activated human CD4+ and CD8+ T lymphocytes. BRB-E also limited in vitro expansion of myeloid-derived suppressor cells (MDSC) and their suppressive capacity. Pre-treatment of immune cells with BRB-E attenuated IL-6-mediated phosphorylation of signal transducer and activator of transcription-3 (STAT3) and IL-2-induced STAT5 phosphorylation. In contrast, pre-treatment of immune cells with the C3R and Q3R metabolites inhibited MDSC expansion, IL-6-mediated STAT3 signaling, but not IL-2-induced STAT5 phosphorylation and were less potent inhibitors of T cell viability. Together these data indicate that BRB extracts and their physiologically relevant metabolites contain phytochemicals that affect immune processes relevant to carcinogenesis and immunotherapy. Furthermore, specific BRB components and their metabolites may be a source of lead compounds for drug development that exhibits targeted immunological outcomes or inhibition of specific STAT-regulated signaling pathways.

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Abbreviations

BRB:

Black raspberry

BRB-E:

Black raspberry extract

C3R:

Cyanidin-3-Rutinoside

MDSC:

Myeloid-derived suppressor cell

Q3R:

Quercitin-3-rutinoside

STAT3:

Signal transducer and activator of transcription 3

STAT5:

Signal transducer and activator of transcription 5

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Acknowledgments

We thank the Ohio State Comprehensive Cancer Center (OSUCCC) Analytical Cytometry, Biostatistics Shared Resources and Nutrient and Phytochemical Analytical Shared Resource (NPASR). Supported by NIH grants 5T32CA009338-34, UL1 RR025755, P30 CA016058, 1R01 CA 169363-01, the Ohio Agricultural Research and Development Center (OARDC), The Center for Advanced Functional Foods Research and Entrepreneurship (CAFFRE), The Food Innovation Center, The OSUCCC Molecular Carcinogenesis and Chemoprevention Program. This work was also supported by the Pelotonia Fellowship Program. Any opinions, findings, and conclusions expressed in this material are those of the authors and do not necessarily reflect those of the Pelotonia Fellowship Program.

Conflict of interest

G Lesinski receives research funding from Prometheus, Inc., Karyopharm Therapeutics, Inc., Oncolytics, Inc, and Array Biopharma, Inc. G Lesinski serves as a Consultant for Ono Pharmaceuticals, Inc. G Lesinski has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. All other authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, 302B Comprehensive Cancer Center, 400 W. 12th Ave., Columbus, OH, 43210, USA

    Thomas A. Mace, Samantha A. King, Zeenath Ameen, Omar Elnaggar, Steven K. Clinton & Gregory B. Lesinski

  2. Center for Biostatistics, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA

    Gregory Young

  3. Department of Food Science and Technology, The Ohio State University, Columbus, OH, USA

    Kenneth M. Riedl & Steven J. Schwartz

  4. College of Public Health, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    Thomas J. Knobloch & Christopher M. Weghorst

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  1. Thomas A. Mace
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  2. Samantha A. King
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  3. Zeenath Ameen
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  9. Thomas J. Knobloch
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Correspondence to Gregory B. Lesinski.

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Mace, T.A., King, S.A., Ameen, Z. et al. Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling. Cancer Immunol Immunother 63, 889–900 (2014). https://doi.org/10.1007/s00262-014-1564-5

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