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Ezrin Contributes to the Plasma Membrane Expression of PD-L1 in A2780 Cells
Mayuka Tameishi1, Honami Ishikawa1, Chihiro Tanaka1
1Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi 584-8540, Japan.
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.
Insights
Ezrin influences programmed death ligand-1 (PD-L1) cell surface levels in ovarian cancer. Targeting ezrin may enhance immune checkpoint inhibitor therapy effectiveness for ovarian cancer patients.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Programmed death ligand-1 (PD-L1) is a key immune checkpoint molecule on cancer cells, regulating T-cell responses.
- Immune checkpoint inhibitors (ICIs) targeting PD-L1 show efficacy, but ovarian cancer patients often have poor responses.
- High PD-L1 expression in advanced ovarian cancer correlates with reduced survival, necessitating strategies to improve ICI therapy.
Purpose of the Study:
- To investigate the role of the ezrin/radixin/moesin (ERM) protein family in regulating PD-L1 plasma membrane expression in ovarian cancer.
- To identify potential therapeutic targets for enhancing ICI efficacy in ovarian cancer.
Main Methods:
- Analysis of PD-L1 and ERM family (ezrin, radixin, moesin) mRNA and protein expression in A2780 human epithelial ovarian cancer cells.
- Assessment of PD-L1 and ERM protein colocalization at the plasma membrane using immunofluorescence.
- Gene silencing of ERM proteins via RNA interference to evaluate effects on PD-L1 plasma membrane expression.
Main Results:
- PD-L1 and all three ERM proteins were expressed at both mRNA and protein levels in A2780 cells.
- PD-L1 showed high colocalization with ezrin and moesin, and moderate colocalization with radixin at the plasma membrane.
- Silencing ezrin, but not radixin or moesin, significantly decreased PD-L1 plasma membrane expression without affecting PD-L1 mRNA levels.
Conclusions:
- Ezrin plays a crucial role in mediating PD-L1 plasma membrane expression in ovarian cancer cells, likely by acting as a scaffold protein.
- Ezrin represents a potential therapeutic target to overcome resistance and improve the efficacy of anti-PD-L1 immune checkpoint inhibitors in ovarian cancer.
