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

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.