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Cancer Immunology, Immunotherapy

, Volume 60, Issue 9, pp 1269–1279 | Cite as

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

  • Bethany L. Mundy-Bosse
  • Gregory S. Young
  • Todd Bauer
  • Elaine Binkley
  • Mark Bloomston
  • Matthew A. Bill
  • Tanios Bekaii-Saab
  • William E. CarsonIII
  • Gregory B. Lesinski
Original article

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+HLADRCD11b+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+HLADRCD15+ MDSC (P = 0.008) and IL-10 with CD33+HLADRCD15 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+HLADRCD15 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.

Keywords

Myeloid-derived suppressor cell Immune suppression Interleukin-6 Interleukin-10 

Notes

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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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Bethany L. Mundy-Bosse
    • 1
    • 5
  • Gregory S. Young
    • 2
    • 5
  • Todd Bauer
    • 3
    • 5
  • Elaine Binkley
    • 3
    • 5
  • Mark Bloomston
    • 4
    • 5
  • Matthew A. Bill
    • 3
    • 5
  • Tanios Bekaii-Saab
    • 3
    • 5
  • William E. CarsonIII
    • 4
    • 5
  • Gregory B. Lesinski
    • 3
    • 5
  1. 1.Department of Integrated Biomedical SciencesThe Ohio State UniversityColumbusUSA
  2. 2.The Center for BiostatisticsThe Ohio State UniversityColumbusUSA
  3. 3.Department of Internal MedicineThe Ohio State UniversityColumbusUSA
  4. 4.Department of SurgeryThe Ohio State UniversityColumbusUSA
  5. 5.Arthur G. James Cancer Hospital and Richard J. Solove Research InstituteColumbusUSA

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