Ezrin and Radixin Differentially Modulate Cell Surface Expression of Programmed Death Ligand-1 in Human Pancreatic Ductal Adenocarcinoma KP-2 Cells
Ezrin and Radixin Differentially Modulate Cell Surface Expression of Programmed Death Ligand-1 in Human Pancreatic Ductal Adenocarcinoma KP-2 Cells
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DOI：
10.3390/immuno2010006
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发表时间：
2022-03-01
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影响因子：
--
通讯作者：
Obata, Tokio
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作者：
Kobori, Takuro;Doukuni, Rina;Obata, Tokio
免疫检查点阻断（ICB）疗法，如针对程序性死亡配体-1（PD-L1）的免疫检查点抑制剂，在治疗胰腺导管腺癌（PDAC）患者方面尚未取得成功。尽管PD-L1在各种类型的癌症中起着关键作用，但PD-L1在PDAC细胞表面表达的调控机制仍知之甚少。因此，发现PD-L1细胞表面定位的潜在调节剂可能为改善PDAC患者的ICB治疗提供新的策略。在这里，我们研究了ezrin/radixin/moesin（ERM）家族支架蛋白在KP-2细胞（一种人PDAC细胞系）中PD-L1表面定位中与肌动蛋白细胞骨架交联跨膜蛋白的作用。我们的研究结果表明，PD-L1，ezrin和radixin的丰富的蛋白质表达，但没有膜突蛋白，以及它们在质膜中的共定位。有趣的是，免疫沉淀分析检测到PD-L1与ezrin和radixin的分子相互作用。此外，ezrin的基因沉默适度地降低了PD-L1的mRNA和细胞表面表达，而radixin的基因沉默极大地降低了PD-L1的表面表达而不改变mRNA水平。因此，radixin和ezrin差异调节KP-2细胞中PD-L1的细胞表面定位，突出了改善PDAC中当前ICB治疗的潜在治疗靶点。
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.