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GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloid-derived suppressor cells

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Abstract

Recent reports have shown the involvement of tumor burden as well as GM-CSF in supporting myeloid-derived suppressor cells (MDSC). However, it is not known what progenitor cells may differentiate into MDSC in the presence of GM-CSF, and whether FVBN202 transgenic mouse model of spontaneous breast carcinoma may exhibit distinct subset distribution of CD11b+Gr1+ cells. In addition, it is not known why CD11b+Gr1+ cells derived from tumor-free and tumor-bearing animals exhibit different functions. In this study, we determined that GM-CSF was one of the tumor-derived soluble factors that induced differentiation of CD11b-Gr1- progenitor cells from within monocytic/granulocytic bone marrow cells into CD11b+Gr1+ cells. We also showed that CD11b+Gr1+ cells in FVBN202 mice consisted of CD11b+Ly6G-Ly6C+ suppressive and CD11b+Ly6G+Ly6C+ non-suppressive subsets. Previously reported variations between tumor-free and tumor-bearing animals in the function of their CD11b+Gr1+ cells were found to be due to the variations in the proportion of these two subsets. Therefore, increasing ratios of CD11b+Gr1+ cells derived from tumor-free animals revealed their suppressive activity on T cells, in vitro. Importantly, GM-CSF supported the generation of CD11b+Ly6G-Ly6C+ suppressor subsets that inhibited proliferation as well as anti-tumor function of neu-specific T cells. These findings suggest revisiting the use of GM-CSF for the expansion of dendritic cells, ex vivo, for cell-based immunotherapy or as an adjuvant for vaccines for patients with cancer in whom MDSC play a major role in the suppression of anti-tumor immune responses.

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Acknowledgments

This work was supported by NIH R01 CA104757 grant (M. H. Manjili) and Department of Defense Grant BC083048. We thank Julie Farnsworth for her expertise in cell sorting and immense dedication to furthering the research at our institution. Flow Cytometry supported in part by NIH Grant P30 CA16059. We gratefully acknowledge the support of VCU Massey Cancer Centre and the Commonwealth Foundation for Cancer Research.

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Authors and Affiliations

  1. Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Massey Cancer Center, Box 980035, 401 College St., Richmond, VA, 23298, USA

    Johanna K. Morales, Maciej Kmieciak & Masoud H. Manjili

  2. Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Keith L. Knutson

  3. Department of Surgery, Virginia Commonwealth University School of Medicine, Massey Cancer Center, Richmond, VA, 23298, USA

    Harry D. Bear

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  1. Johanna K. Morales
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  2. Maciej Kmieciak
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  3. Keith L. Knutson
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  5. Masoud H. Manjili
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Correspondence to Masoud H. Manjili.

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Morales, J.K., Kmieciak, M., Knutson, K.L. et al. GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloid-derived suppressor cells. Breast Cancer Res Treat 123, 39–49 (2010). https://doi.org/10.1007/s10549-009-0622-8

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  • DOI: https://doi.org/10.1007/s10549-009-0622-8

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