Insulin-like Growth Factors Inhibit Dendritic Cell-Mediated Anti-tumor Immunity in Epithelial Ovarian Cancer
Date Issued
2015
Date
2015
Author(s)
Huang, Ching-Ting
Abstract
Insulin-like growth factors (IGFs) can promote tumorigenesis via stimulating cell proliferation and inhibiting the apoptosis of cancer cells. The relationship and the possible mechanism between IGFs and dendritic cell (DC)-mediated immunity were investigated. Advanced-stage epithelial ovarian cancer (EOC) patients were evaluated to show higher IGF-1 and IGF-2 concentrations in their ascites than early-stage patients. In addition, concentrations of IGF-1 also positively correlated with IL-2, IL-6, IL-10, IL-12 and TNF-α cytokines in early-stage EOC patients, but not in advanced-stage. There was no strong correlation between IGF-2 and the cytokines in the early-stage and advanced-stage EOC patients. To elucidate the exact function of IGFs on host immunity and especially with respect to DCs, bone marrow monocyte -derived DCs were first acquired and cultured with GM-CSF and IGFs from immune-competent mice. The maturation status and functions of IGF-treated DCs were analyzed. IGFs could suppress DCs'' maturation, antigen presenting abilities, and the ability to activate antigen-specific CD8+ cytotoxic T cells. IGF-treated DCs also secreted higher concentrations of IL-10 and TNF-α. IGF-treated DCs showed decreased ERK1/2 phosphorylation and reduced p38 dephosphorylation. The percentages of matured DCs in the ascites were significantly lower in the IGF-1 or IGF-2 highly-expressing WF-3 tumor-bearing mice. The IGF1R inhibitor NVP-AEW541 could block the effects of IGFs to rescue DCs'' maturation and to restore DC-mediated antigen-specific immunity through enhancing ERK1/2 phosphorylation and p38 dephosphorylation. In conclusion, IGFs can inhibit DC-mediated anti-tumor immunity through suppressing maturation and function and the IGF1R inhibitor NVP-AEW541 could restore the DC-mediated anti-tumor immunity. Blockade of IGFs could be a potential strategy for cancer immunotherapy.
Subjects
ascites
dendritic cells
insulin-like growth factor
insulin-like growth factor 1 receptor
ovarian cancer
SDGs
Type
thesis
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