Insulin-like growth factors inhibit dendritic cell-mediated anti-tumor immunity through regulating ERK1/2 phosphorylation and p38 dephosphorylation

Ching-Ting Huang; Ming-Cheng Chang; Yu-Li Chen; Tsung-Ching Chen; Chi-An Chen; Wen-Fang Cheng

doi:10.1016/j.canlet.2015.01.007

Insulin-like growth factors inhibit dendritic cell-mediated anti-tumor immunity through regulating ERK1/2 phosphorylation and p38 dephosphorylation

Cancer Lett. 2015 Apr 1;359(1):117-26. doi: 10.1016/j.canlet.2015.01.007. Epub 2015 Jan 12.

Authors

Ching-Ting Huang¹, Ming-Cheng Chang², Yu-Li Chen³, Tsung-Ching Chen², Chi-An Chen², Wen-Fang Cheng⁴

Affiliations

¹ Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan.
³ Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan.
⁴ Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: wenfangcheng@yahoo.com.

PMID: 25592043
DOI: 10.1016/j.canlet.2015.01.007

Abstract

Insulin-like growth factors (IGFs) can promote tumorigenesis via inhibiting the apoptosis of cancer cells. The relationship between IGFs and dendritic cell (DC)-mediated immunity were investigated. Advanced-stage ovarian carcinoma patients were first evaluated to show higher IGF-1 and IGF-2 concentrations in their ascites than early-stage patients. IGFs could suppress DCs' maturation, antigen presenting abilities, and the ability to activate antigen-specific CD8(+) T cell. 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. IGFs can inhibit DC-mediated anti-tumor immunity through suppressing maturation and function and the IGF1R inhibitor could restore the DC-mediated anti-tumor immunity. Blockade of IGFs could be a potential strategy for cancer immunotherapy.

Keywords: Antigen presenting; Dendritic cells; IGF1R; Insulin-like growth factor; NVP-AEW541.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Ascites / metabolism
Cell Line, Tumor
Coculture Techniques
Dendritic Cells / drug effects
Dendritic Cells / enzymology*
Dendritic Cells / immunology
Female
Humans
Immunity, Cellular* / drug effects
Insulin-Like Growth Factor I / genetics
Insulin-Like Growth Factor I / metabolism*
Insulin-Like Growth Factor II / genetics
Insulin-Like Growth Factor II / metabolism*
Interferon-gamma / metabolism
Interleukins / metabolism
Lymphocyte Activation
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 1 / metabolism*
Mitogen-Activated Protein Kinase 3 / metabolism*
Neoplasm Staging
Ovarian Neoplasms / drug therapy
Ovarian Neoplasms / enzymology*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / immunology
Ovarian Neoplasms / pathology
Phosphorylation
Pyrimidines / pharmacology
Pyrroles / pharmacology
Receptor, IGF Type 1 / antagonists & inhibitors
Receptor, IGF Type 1 / metabolism
Signal Transduction
T-Lymphocytes, Cytotoxic / immunology
T-Lymphocytes, Cytotoxic / metabolism
Time Factors
Transfection
Tumor Necrosis Factor-alpha / metabolism
p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

Antineoplastic Agents
IGF1 protein, human
IGF2 protein, human
IGF2 protein, mouse
Interleukins
NVP-AEW541
Pyrimidines
Pyrroles
Tumor Necrosis Factor-alpha
insulin-like growth factor-1, mouse
Insulin-Like Growth Factor I
Insulin-Like Growth Factor II
Interferon-gamma
Receptor, IGF Type 1
Mapk1 protein, mouse
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
p38 Mitogen-Activated Protein Kinases