Insulin-like growth factor-1 receptor induces immunosuppression in lung cancer by upregulating B7-H4 expression through the MEK/ERK signaling pathway

Zhiming Zhao; Ningyue Zhang; Anqi Li; Bin Zhou; Yali Chen; Shaomu Chen; Moli Huang; Fengying Wu; Liang Zhang

doi:10.1016/j.canlet.2020.04.013

Insulin-like growth factor-1 receptor induces immunosuppression in lung cancer by upregulating B7-H4 expression through the MEK/ERK signaling pathway

Cancer Lett. 2020 Aug 10:485:14-26. doi: 10.1016/j.canlet.2020.04.013. Epub 2020 May 14.

Authors

Zhiming Zhao¹, Ningyue Zhang¹, Anqi Li¹, Bin Zhou², Yali Chen¹, Shaomu Chen³, Moli Huang⁴, Fengying Wu⁵, Liang Zhang⁶

Affiliations

¹ College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
² Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Soochow University, Suzhou, Jiangsu, China.
³ Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
⁴ Department of Bioinformatics, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China.
⁵ Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: 1701823@tongji.edu.cn.
⁶ College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China; Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Soochow University, Suzhou, Jiangsu, China. Electronic address: zliang@suda.edu.cn.

PMID: 32417396
DOI: 10.1016/j.canlet.2020.04.013

Abstract

The Insulin-like growth factor-1/Insulin-like growth factor-1 receptor (IGF1/IGF1R) axis contributes to immunosuppression during tumor progression; however, the underlying mechanism remains unclear. In the present study, we found that IGF1 stimulation or IGF1R overexpression (IGF1R-OE) could upregulate the expression of B7-H4, while IGF1R inhibition downregulated B7-H4 in both A549 and SPC-A-1 lung cancer cell lines. IGF1R-OE conferred the inhibition of CD8⁺ T cells by cancer cells in vitro, and induction of B7-H4 expression was mediated by the activation of the MEK/ERK1/2 signaling pathway. The in vitro findings were further confirmed in vivo using a Lewis lung cancer mouse model. IGF1R-OE promoted tumor growth and inhibited tumor infiltration by CD8⁺ T cells in the mouse model. However, this effect was suppressed when B7-H4 was knocked down in IGF1R-OE cells. Our findings suggest that IGF1R could induce immunosuppression in lung cancer by upregulating the expression of B7-H4 through the MEK/ERK pathway. B7-H4 may therefore be a potential therapeutic target for lung cancer immunotherapy.

Keywords: B7-H4 (VTCN1); CD8(+) T cell; Insulin-like growth factor-1 receptor (IGF1R); Lung cancer; MEK/ERK.

Publication types

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

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
CD8-Positive T-Lymphocytes / immunology
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Humans
Immune Tolerance*
Lung Neoplasms / drug therapy
Lung Neoplasms / immunology*
MAP Kinase Signaling System / drug effects
MAP Kinase Signaling System / physiology*
Male
Mice
Mice, Inbred C57BL
Middle Aged
Receptor, IGF Type 1 / physiology*
V-Set Domain-Containing T-Cell Activation Inhibitor 1 / genetics*

Substances

IGF1R protein, human
V-Set Domain-Containing T-Cell Activation Inhibitor 1
VTCN1 protein, human
Receptor, IGF Type 1