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Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signaling in CD4+ T cells from patients with GI malignancy

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Abstract

Interferon-alpha (IFN-α) promotes anti-tumor immunity through its actions on immune cells. We hypothesized that elevated percentages of myeloid-derived suppressor cells (MDSC) and increased pro-inflammatory cytokines in peripheral blood would be associated with impaired response to IFN-α in patients with gastrointestinal (GI) malignancies. This study evaluated relationships between plasma IL-6, IL-10, circulating MDSC subsets, and IFN-α-induced signal transduction in 40 patients with GI malignancies. Plasma IL-6 and IL-10 were significantly higher in patients versus normal donors. CD33+HLADR−CD11b+CD15+ and CD33+HLADR−/lowCD14+ MDSC subsets were also elevated in patients versus normal donors (P < 0.0001). Plasma IL-6 was correlated with CD33+HLADR−CD15+ MDSC (P = 0.008) and IL-10 with CD33+HLADR−CD15− MDSC (P = 0.002). The percentage of CD15+ and CD15− but not CD14+ MDSC subsets were inversely correlated with IFN-α-induced STAT1 phosphorylation in CD4+ T cells, while co-culture with in vitro generated MDSC led to reduced IFN-α responsiveness in both PBMC and the CD4+ subset of T cells from normal donors. Exploratory multivariable Cox proportional hazards models revealed that an increased percentage of the CD33+HLADR−CD15− MDSC subset was associated with reduced overall survival (P = 0.049), while an increased percentage of the CD33+HLADR−/lowCD14+ subset was associated with greater overall survival (P = 0.033). These data provide evidence for a unique relationship between specific cytokines, MDSC subsets, and IFN-α responsiveness in patients with GI malignancies.

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Acknowledgments

We thank Dr. Susan Geyer for critical review of this manuscript. We thank the OSU CCC Analytical Cytometry Shared Resource. We would also like to thank the following agencies for grant support: The Valvano Foundation for Cancer Research Award (to G.B. Lesinski), National Institutes of Health (NIH) Grants T32 GM068412 (to B. Mundy), CA84402, K24 CA93670 (to W.E. Carson), K22 CA134551 (to G.B. Lesinski), and The Samuel J. Roessler Memorial Scholarship at The Ohio State University College of Medicine (to E. Binkley).

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Authors and Affiliations

  1. Department of Integrated Biomedical Sciences, The Ohio State University, Columbus, OH, USA

    Bethany L. Mundy-Bosse

  2. The Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    Gregory S. Young

  3. Department of Internal Medicine, The Ohio State University, 302B Comprehensive Cancer Center/Wiseman Hall, 400 W. 12th Ave, Columbus, OH, 43210, USA

    Todd Bauer, Elaine Binkley, Matthew A. Bill, Tanios Bekaii-Saab & Gregory B. Lesinski

  4. Department of Surgery, The Ohio State University, N911 Doan Hall, 410 W. 10th Ave, Columbus, OH, 43210, USA

    Mark Bloomston & William E. Carson III

  5. Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, 43210, USA

    Bethany L. Mundy-Bosse, Gregory S. Young, Todd Bauer, Elaine Binkley, Mark Bloomston, Matthew A. Bill, Tanios Bekaii-Saab, William E. Carson III & Gregory B. Lesinski

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  1. Bethany L. Mundy-Bosse
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Correspondence to William E. Carson III or Gregory B. Lesinski.

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Mundy-Bosse, B.L., Young, G.S., Bauer, T. et al. Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signaling in CD4+ T cells from patients with GI malignancy. Cancer Immunol Immunother 60, 1269–1279 (2011). https://doi.org/10.1007/s00262-011-1029-z

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