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. Carson, Gregory B. Lesinski

Research output: Contribution to journalArticle

95 Scopus citations

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 -/low CD14 + 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.

Original languageEnglish (US)
Pages (from-to)1269-1279
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume60
Issue number9
DOIs
StatePublished - Sep 2011

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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