Amphiregulin Confers Regulatory T Cell Suppressive Function and Tumor Invasion via the EGFR/GSK-3β/Foxp3 Axis

Abstract Previous studies mainly focused on the role of Epidermal growth factor receptor (EGFR) in tumor cells, while the effects of EGFR on immune responses has not been determined. Our study shown that EGFR signaling pathway play a role in regulation of Treg cells in cancer patients. The EGF-like growth factor Amphiregulin (AREG) protein was frequently upregulated in tissue microarray and in sera, tissue specimen and effusion of lung cancer and gastric cancer patients and upregulated AREG protein was associated with worse overall survival and enhanced the suppressive function of Treg cells. AREG maintained the Treg cells suppressive function via the EGFR/GSK-3β/Foxp3 axis in vitro and in vivo. Furthermore, inhibition of EGFR by tyrosine kinase inhibitor gefitinib restored the activity of GSK-3β and attenuated Treg cell functions. β-TrCP was involved in GSK-3β-mediated Foxp3 degradation and mass spectrometry identifies Lys356 as the ubiquitination site of Foxp3 by β-TrCP. These findings demonstrated the posttranslational regulation of Foxp3 expression by AREG in cancer patients through the AREG/EGFR/GSK3β signaling, which could lead to Foxp3 protein degradation in Treg cells and a potential therapeutic target for cancer treatment.