Contribution of Ezrin on the Cell Surface Plasma Membrane Localization of Programmed Cell Death Ligand-1 in Human
Mayuka Tameishi1, Takuro Kobori1, Chihiro Tanaka1
1Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan.
Abstract:
Immune checkpoint blockade (ICB) antibodies targeting programmed cell death ligand-1 (PD-L1) and programmed cell death-1 (PD-1) have improved survival in patients with conventional single agent chemotherapy-resistant gestational trophoblastic neoplasia (GTN). However, many patients are resistant to ICB therapy, the mechanisms of which are poorly understood. Unraveling the regulatory mechanism for PD-L1 expression may provide a new strategy to improve ICB therapy in patients with GTN. Here, we investigated whether the ezrin/radixin/moesin (ERM) family, i.e., a group of scaffold proteins that crosslink actin cytoskeletons with several plasma membrane proteins, plays a role in the regulation of PD-L1 expression using JEG-3 cells, a representative human choriocarcinoma cell line. Our results demonstrate mRNA and protein expressions of ezrin, radixin, and PD-L1, as well as their colocalization in the plasma membrane. Intriguingly, immunoprecipitation experiments revealed that PD-L1 interacted with both ezrin and radixin and the actin cytoskeleton. Moreover, gene silencing of ezrin but not radixin strongly diminished the cell surface expression of PD-L1 without altering the mRNA level. These results indicate that ezrin may contribute to the cell surface localization of PD-L1 as a scaffold protein in JEG-3 cells, highlighting a potential therapeutic target to improve the current ICB therapy in GTN.
Insights
Ezrin, a scaffold protein, helps regulate PD-L1 cell surface expression in gestational trophoblastic neoplasia (GTN). This finding offers a potential new strategy to improve immune checkpoint blockade (ICB) therapy for GTN patients resistant to current treatments.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Immune checkpoint blockade (ICB) targeting PD-L1/PD-1 improves survival in chemotherapy-resistant gestational trophoblastic neoplasia (GTN).
- Resistance to ICB therapy in GTN is a significant clinical challenge, with underlying mechanisms poorly understood.
- Identifying novel regulatory pathways for PD-L1 expression could enhance ICB efficacy in GTN.
Purpose of the Study:
- To investigate the role of the ezrin/radixin/moesin (ERM) protein family in regulating programmed cell death ligand-1 (PD-L1) expression in GTN.
- To explore the interaction between ERM proteins, PD-L1, and the actin cytoskeleton in JEG-3 choriocarcinoma cells.
Main Methods:
- Analysis of mRNA and protein expression of ezrin, radixin, and PD-L1 in JEG-3 cells.
- Immunoprecipitation assays to determine protein interactions and colocalization at the plasma membrane.
- Gene silencing of ezrin and radixin to assess their impact on PD-L1 cell surface expression.
Main Results:
- Ezrin, radixin, and PD-L1 were expressed and colocalized at the plasma membrane in JEG-3 cells.
- PD-L1 was found to interact with ezrin, radixin, and the actin cytoskeleton.
- Silencing ezrin, but not radixin, significantly reduced PD-L1 cell surface expression without affecting its mRNA levels.
Conclusions:
- Ezrin acts as a scaffold protein, potentially facilitating the cell surface localization of PD-L1 in GTN cells.
- Targeting ezrin may represent a novel therapeutic strategy to overcome ICB resistance in gestational trophoblastic neoplasia.
- Further research into the ezrin-PD-L1 interaction could optimize ICB therapy for GTN patients.
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