Abstract 5517: Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-α signal transduction in CD4+ T cells from patients with gastrointestinal malignancy

Abstract

Abstract Interferon-alpha (IFNα) can promote anti-tumor immunity through its actions on immune cells. We have shown in murine models that a class of immune suppressor cells known as myeloid-derived suppressor cells (MDSC) have inhibitory effects on IFN signal transduction and gene regulation. Interleukin (IL)-6 and IL-10 are produced by tumor cells in cancer patients and can regulate the survival and function of MDSC. This study evaluated relationships between plasma IL-6, IL-10, circulating MDSC subsets and IFNα-induced signal transduction in 40 patients with gastrointestinal (GI) malignancies. Plasma IL-6 and IL-10 levels were significantly higher in patients versus normal donors. CD33+HLADR−CD11b+CD15+ and CD33+HLADR−/lowCD14+ MDSC were also elevated in patients versus normal donors (p<0.0001). Prior studies suggest that CD15 divides human MDSC into granulocytic (CD15+) and monocytic (CD15−) subsets. Therefore relationships between CD15 expression on MDSC and cytokines elevated in GI patients were examined. A significant correlation between plasma IL-6 with CD33+HLADRCD15+ MDSC (p=0.008) and IL10 with CD33+HLADR−CD15− MDSC (p=0.002) was observed. The level of CD15+ and CD15− but not CD14+ MDSC subsets were inversely correlated with IFNα-induced STAT1 phosphorylation in CD4+ T cells, while co-culture with in vitro generated MDSC led to reduced IFNα-responsiveness in PBMC from normal donors. In a multivariable Cox proportional hazards model, an increased percentage of the CD33+HLADR−CD15− MDSC subset was associated with reduced overall survival (hazard ratio = 1.43; p = 0.049) while an increased percentage of the CD33+HLADR−/lowCD14+ subset was associated with greater overall survival (hazard ratio = 0.69, p=0.033). These data provide evidence for a unique relationship between specific cytokines, MDSC subsets and IFNα responsiveness in patients with GI malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5517. doi:10.1158/1538-7445.AM2011-5517