IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway in malignant melanoma

• Published in: Cancer letters 2020-05, Vol.477, p.19-30
• Main Authors: Li, Ting, Zhang, Chao, Zhao, Gang, Zhang, Xinwei, Hao, Mengze, Hassan, Shafat, Zhang, Min, Zheng, Hong, Yang, Da, Liu, Liang, Mehraein-Ghomi, Farideh, Bai, Xu, Chen, Kexin, Zhang, Wei, Yang, Jilong
• Format: Article
• Language: English
• Subjects: Anti-PD-1; Antibodies; Antibodies, Monoclonal, Humanized - therapeutic use; Antitumor activity; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Biotechnology; Cancer therapies; Cell Line, Tumor; Cell Nucleus - metabolism; Drug resistance; Epidermal growth factor receptors; ErbB Receptors - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Growth factors; Humans; IGFBP2; Immune system; Immunotherapy; Insulin-Like Growth Factor Binding Protein 2 - genetics; Insulin-Like Growth Factor Binding Protein 2 - metabolism; Insulin-like growth factor-binding protein 2; Kaplan-Meier Estimate; Kinases; Ligands; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - mortality; Molecular Targeted Therapy; PD-1 protein; PD-L1; PD-L1 protein; Proteins; Signal Transduction; Skin cancer; Stat3 protein; STAT3 Transcription Factor - metabolism; Tumors
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2020.02.036

Immunotherapy targeting the PD-1/PD-L1 receptor has achieved great success in melanoma patients. Although many studies have addressed the underlying mechanisms involved in the blockade of PD-1/PD-L1 and the consequent modulation of the immune system, the mechanisms of PD-L1 upregulation and reliable biomarkers to predict the efficacy of anti-PD-1/PD-L1 therapy remain unknown. The present study demonstrates the correlation between IGFBP2 and PD-L1, revealing a novel immune-associated tumor function of IGFBP2 in facilitating nuclear accumulation of EGFR and activation of the EGFR/STAT3/PD-L1 signaling pathway in melanoma cells. Our results also suggest that combined IGFBP2 and PD-L1 expression has the potential to predict the efficacy of anti-PD-1 treatment for malignant melanoma; because the combination of high IGFBP2 and PD-L1 expression characterizes melanoma patients with worse overall survival and is associated with a better immune ecosystem. These characteristics have been confirmed by both in vitro and in vivo data. Consequently, IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway and its function as a PD-L1 regulator might suggest novel therapeutic approach for melanoma. •IGFBP2 and PD-L1 are highly expressed in melanoma and predict poor prognosis.•IGFBP2 regulates PD-L1 expression by promoting EGFR nuclear accumulation and EGFR/STAT3 activation in melanoma cells.•Combined IGFBP2 and PD-L1 expression have the potential to predict the efficacy of anti-PD-1 treatment in melanoma.