期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 60, 期 9, 页码 1269-1279出版社
SPRINGER
DOI: 10.1007/s00262-011-1029-z
关键词
Myeloid-derived suppressor cell; Immune suppression; Interleukin-6; Interleukin-10
资金
- Valvano Foundation for Cancer Research
- National Institutes of Health (NIH) [T32 GM068412, CA84402, K24 CA93670, K22 CA134551]
- Ohio State University College of Medicine
Interferon-alpha (IFN-alpha) 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-alpha in patients with gastrointestinal (GI) malignancies. This study evaluated relationships between plasma IL-6, IL-10, circulating MDSC subsets, and IFN-alpha-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(-/low)CD14(+) 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-alpha-induced STAT1 phosphorylation in CD4(+) T cells, while co-culture with in vitro generated MDSC led to reduced IFN-alpha 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-alpha responsiveness in patients with GI malignancies.
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