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

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.