Abstract
Programmed death ligand–1 (PD–L1) is one of the immune checkpoint molecule localized on the plasma membrane of numerous cancer cells that negatively regulates T-cell-mediated immunosurveillance. Despite the remarkable efficacy and safety profile of immune checkpoint inhibitors (ICIs), such as anti-PD–L1 antibodies, restricted poor therapeutic responses to ICIs are often observed in patients with ovarian cancer. Because higher expression of PD–L1 in advanced ovarian cancer is associated with a decreased survival rate, identifying the potential molecules to regulate the plasma membrane expression of PD–L1 may provide a novel therapeutic strategy to improve the efficacy of ICIs against ovarian cancers. Here, we reveal the involvement of the ezrin/radixin/moesin (ERM) family, which crosslinks transmembrane proteins with the actin cytoskeleton by serving as a scaffold protein, in the plasma membrane expression of PD–L1 in the human epithelial ovarian cancer cell line A2780. Our results demonstrate that PD–L1 and all three ERMs were expressed at the mRNA and protein levels in A2780 cells, and that PD–L1 was highly colocalized with ezrin and moesin, but moderately with radixin, in the plasma membrane. Interestingly, RNA interference-mediated gene silencing of ezrin, but not of radixin or moesin, substantially reduced the plasma membrane expression of PD–L1 without altering its mRNA expression. In conclusion, our results indicate that ezrin may be responsible for the plasma membrane expression of PD–L1, possibly by serving as a scaffold protein in A2780 cells. Ezrin is a potential therapeutic target for improving the efficacy of ICIs against ovarian cancers.