Abstract
Immune checkpoint blockade (ICB) therapies, such as immune checkpoint inhibitors against programmed death ligand-1 (PD-L1), have not been successful in treating patients with pancreatic ductal adenocarcinoma (PDAC). Despite the critical role of PD-L1 in various types of cancers, the regulatory mechanism of PD-L1 expression on the cell surface of PDAC is poorly understood. Therefore, uncovering potential modulators of cell surface localisation of PD-L1 may provide a new strategy to improve ICB therapy in patients with PDAC. Here, we examined the role of ezrin/radixin/moesin (ERM) family scaffold proteins that crosslink transmembrane proteins with the actin cytoskeleton in the surface localisation of PD-L1 in KP-2 cells, a human PDAC cell line. Our results demonstrated the abundant protein expression of PD-L1, ezrin, and radixin, but not moesin, as well as their colocalisation in the plasma membrane. Interestingly, immunoprecipitation analysis detected the molecular interaction of PD-L1 with ezrin and radixin. Moreover, gene silencing of ezrin moderately decreased the mRNA and cell surface expression of PD-L1, while that of radixin greatly decreased the surface expression of PD-L1 without altering the mRNA levels. Thus, radixin and ezrin differentially modulate the cell surface localisation of PD-L1 in KP-2 cells, highlighting a potential therapeutic target to improve the current ICB therapy in PDAC.
Highlights
Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Laboratory of Natural Medicines, Faculty of Pharmacy, Osaka Ohtani University, Abstract: Immune checkpoint blockade (ICB) therapies, such as immune checkpoint inhibitors against programmed death ligand-1 (PD-L1), have not been successful in treating patients with pancreatic ductal adenocarcinoma (PDAC)
Moesin was undetectable at the protein level in whole cell lysates of KP-2 cells, but was strongly detected in HeLa cells, a human uterine cervical adenocarcinoma cell line used as a positive control in which moesin is present at high abundance [35,36], which is in accordance with the present results (Figure 1c)
Our Confocal Laser Scanning Microscopy (CLSM) analysis data clearly implied that the fluorescence signals of PD-L1, ezrin, and radixin were distributed in the plasma membrane, resulting in the colocalisation of PD-L1 with ezrin and radixin, but those of moesin were hardly detectable in KP-2 cells
Summary
Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Laboratory of Natural Medicines, Faculty of Pharmacy, Osaka Ohtani University, Abstract: Immune checkpoint blockade (ICB) therapies, such as immune checkpoint inhibitors against programmed death ligand-1 (PD-L1), have not been successful in treating patients with pancreatic ductal adenocarcinoma (PDAC). Despite the critical role of PD-L1 in various types of cancers, the regulatory mechanism of PD-L1 expression on the cell surface of PDAC is poorly understood. Uncovering potential modulators of cell surface localisation of PD-L1 may provide a new strategy to improve ICB therapy in patients with PDAC. We examined the role of ezrin/radixin/moesin (ERM) family scaffold proteins that crosslink transmembrane proteins with the actin cytoskeleton in the surface localisation of PD-L1 in KP-2 cells, a human PDAC cell line. Radixin and ezrin differentially modulate the cell surface localisation of PD-L1 in KP-2 cells, highlighting a potential therapeutic target to improve the current ICB therapy in PDAC. (PD-L1), an immune checkpoint molecule frequently expressed on cancer cells that binds to programmed death-1 (PD-1) on T-cells [8]. Despite the huge success of ICB therapy during the past decade in a small subset of many solid tumours [12], limited benefits have emerged in patients with
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