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Insulin-like Growth Factors Inhibit Dendritic Cell-Mediated Anti-tumor Immunity through Regulation of ERK1/2 Phosphorylation and P38 Dephosphorylation

Huang, Ching-Ting and Chang, Ming-Cheng and Chen, Yu-Li and Chen, Tsung-Ching and Chen, Chi-An and Cheng, Wen-Fang (2015) Insulin-like Growth Factors Inhibit Dendritic Cell-Mediated Anti-tumor Immunity through Regulation of ERK1/2 Phosphorylation and P38 Dephosphorylation. Cancer Letters.

Abstract

Insulin-like growth factors (IGFs) can promote tumorigenesis via inhibiting the apoptosis of cancer cells. However, whether IGFs can regulate host immunity to promote tumorigenesis has yet to be elucidated. Therefore, we investigated the relationship between IGFs and dendritic cell (DC)-mediated immunity. We first identified that advanced-staged ovarian carcinoma patients had higher IGF-1 IGF-2, IL-6, and IL-10 concentrations in their ascites than early-staged patients, and the
concentrations of IL-6 and IL-10 were found to be positively correlated with IGF-1 and IGF-2, respectively. IGFs could suppress the maturation and antigen presenting abilities of the DCs. The ability to activate antigen-specific CD8+ T cells by IGF-1 and/or IGF-2-treated DCs was lower than the control group. The concentrations of IL-10 and TNFα in IGF-1 and/or IGF-2-treated DCs were significantly higher than the control group. The IGF-treated DCs showed decreased ERK1/2 phosphorylation and reduced p38 dephosphorylation compared with the PBS-treated group. The
percentages of matured DCs in the ascites were also significantly lower in the IGF-1 or IGF-2 highly-expressing WF-3 tumor-bearing mice than those in the parental WF-3 group. The IGF1R inhibitor, NVP-AEW541, could block the effects of IGFs on the DCs to rescue the maturation of DCs and to restore DC-mediated antigen-specific immunity through enhancing ERK1/2 phosphorylation and p38 dephosphorylation in vitro. Our results indicate that IGFs can inhibit DC-mediated anti-tumor immunity through suppressing maturation and function. The IGF1R inhibitor-NVP-AEW541 could rescue the maturation of DCs and restore the DC-mediated anti-tumor immunity suppressed by IGFs. The blockade of IGFs could be a potential strategy for cancer immunotherapy.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21666

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