Abstract
Immunotherapy using antibodies blocking the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway has achieved great success in preclinical models and the clinical treatment of esophageal squamous cell carcinoma (ESCC). The c-Myc proto-oncogene helps prevent immune cells from attacking tumor cells by inducing PD-L1 expression. However, the underlying mechanisms of c-Myc and PD-L1 in ESCC remain unclear, and a thorough understanding of this regulation would allow the development of new approaches to enhance antitumor immunity. In the present study, the positive relationship between c-Myc and PD-L1 was explored in the Cancer Genome Atlas dataset using the bioinformatics tool GEPIA, and was confirmed in 105 ESCC tissues by immunostaining (r=0.516, P<0.001). The patients positive for both proteins had a poorer overall survival (P=0.032). Furthermore, in ESCC cell lines, c-Myc overexpression, depletion, and inhibition was able to regulate the expression of PD-L1. Also, the ChIP assays showed that the increase in PD-L1 expression was likely due to the binding of c-Myc to the PD-L1 promoter. Taken together, c-Myc and PD-L1 levels were significantly correlated, and c-Myc expression regulated the expression of PD-L1 in ESCC cells. In addition, a small molecule inhibitor of c-Myc effectively regulated PD-L1 expression. This indicates that synergistic therapy combining a c-Myc inhibitor with PD-L1 immunotherapy might be a promising new treatment strategy for ESCC.