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Poly (I: C) modulates the immunosuppressive activity of myeloid-derived suppressor cells in a murine model of breast cancer

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Abstract

Polyinosinic-polycytidylic acid [Poly (I: C)], a ligand for Toll-like receptor (TLR-3), is used as an adjuvant to enhance anti-tumor immunity because of its prominent effects on CD8 T cells and NK cells. Myeloid-derived suppressor cells (MDSCs) are one of the main immunosuppressive factors in cancer, and their abnormal accumulation is correlated with the clinical stage of breast cancer and is an important mechanism of tumor immune evasion. Although Poly (I: C) is thought to have direct anti-tumor activity in different cell lines, its effect on immunosuppressive MDSCs in tumor-bearing animals has not been studied. 4T1-Luc, a metastatic breast cancer mouse cell line, was injected into the left flank of female BALB/c mice. Tumor-bearing mice were treated with i.p. injection of Poly (I: C) or PBS beginning on day 7 after tumor inoculation. WBCs and MDSCs were counted using coulter counter and stained for flow cytometry, respectively. Bioluminescent imaging was used to monitor tumor burden at multiple time points during the course of tumor growth. Poly (I: C) treatment led to a decrease in MDSC frequencies in BM, blood, and tumor compared to saline-treated control mice. Poly (I: C) treatment also abrogated the immunosuppressive function of MDSCs, concomitant with an increase in local T cell response of the immune system in a murine model of breast cancer. Poly (I: C) treatment decreases MDSC frequency and immunosuppressive function in 4T1-tumor-bearing hosts and effectively augments the activity of breast cancer immunotherapy.

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Abbreviations

MDSC:

Myeloid-derived suppressor cells

S.C:

Subcutaneous

I.P:

Intra peritoneal

BLI:

Bioluminescence intensity

ROI:

Regions of interest

Luc:

Luciferase

Lin:

Lineage

FACS:

Fluorescent activated cell sorting

IMC:

Immature myeloid cell

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Acknowledgments

The authors thank Dr. Ragavan Chinnadurai for his guidance; Wayne Harris for his helpful technical assistance in sorting and Christopher Peterson for help in Western blotting. Also author thanks Anthea Hamond for her careful reading and editing of manuscript.

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Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Parvin Forghani & Edmund K. Waller

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  1. Parvin Forghani
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  2. Edmund K. Waller
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Correspondence to Parvin Forghani.

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The authors disclose no potential conflicts of interest.

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10549_2015_3508_MOESM1_ESM.tif

Figure. S1. Poly (I: C) treatment decreases the frequency and absolute numbers of MDSCs 4T1 tumor cells were implanted into the 1st left mammary fat pad of female BALB/c mice (1 × 106 cells per mouse, n = 4 per group). Blood samples were obtained on week three after tumor inoculation. (A) Flow cytometry analysis of blood showing mean percentages of MDSCs and CD3+ T cells in Poly (I: C)-treated and PBS-treated tumor-bearing mice vs. non-tumor bearing Poly (I: C)-treated mice. Mean frequencies (±SD) from three separate experiments. (B) Absolute numbers of MDSCs and CD3+ T cells in the blood after tumor inoculation in two groups. Two-way ANOVA* shows statistically significant differences from control (p < 0.05) from three independent experiments.

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Forghani, P., Waller, E.K. Poly (I: C) modulates the immunosuppressive activity of myeloid-derived suppressor cells in a murine model of breast cancer. Breast Cancer Res Treat 153, 21–30 (2015). https://doi.org/10.1007/s10549-015-3508-y

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  • DOI: https://doi.org/10.1007/s10549-015-3508-y

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