Original article

Cancer Immunology, Immunotherapy

, Volume 60, Issue 9, pp 1269-1279

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-BosseAffiliated withDepartment of Integrated Biomedical Sciences, The Ohio State UniversityArthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • , Gregory S. YoungAffiliated withThe Center for Biostatistics, The Ohio State UniversityArthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • , Todd BauerAffiliated withDepartment of Internal Medicine, The Ohio State UniversityArthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • , Elaine BinkleyAffiliated withDepartment of Internal Medicine, The Ohio State UniversityArthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • , Mark BloomstonAffiliated withDepartment of Surgery, The Ohio State UniversityArthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • , Matthew A. BillAffiliated withDepartment of Internal Medicine, The Ohio State UniversityArthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • , Tanios Bekaii-SaabAffiliated withDepartment of Internal Medicine, The Ohio State UniversityArthur G. James Cancer Hospital and Richard J. Solove Research Institute
  • , William E. CarsonIIIAffiliated withDepartment of Surgery, The Ohio State UniversityArthur G. James Cancer Hospital and Richard J. Solove Research Institute Email author 
  • , Gregory B. LesinskiAffiliated withDepartment of Internal Medicine, The Ohio State UniversityArthur G. James Cancer Hospital and Richard J. Solove Research Institute Email author 

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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+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