Adorisio Sabrina, Renga Giorgia, Delfino Domenico Vittorio, Ayroldi Emira
Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy.
Foligno Nursing School, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy.
Biomedicines. 2025 Jul 22;13(8):1793. doi: 10.3390/biomedicines13081793.
Glucocorticoids (GCs), such as dexamethasone (DEX), are commonly administered to glioblastoma (GBM) patients to control cerebral edema; however, their effects on immune checkpoint regulation in tumor cells remain insufficiently characterized. This study examined the impact of DEX on the expression of programmed death-ligand 1 (PD-L1) and glucocorticoid-induced leucine zipper (GILZ), a downstream effector of glucocorticoid receptor (GR) signaling, in the U87 and U251 glioblastoma cell lines. DEX consistently induced GILZ expression in both models yet elicited divergent effects on PD-L1: suppression in U87 cells and upregulation in U251 cells. In U87 cells, DEX-induced PD-L1 downregulation was accompanied by accelerated cell cycle progression, suggesting a dual impact on tumor immune evasion and proliferation. Mechanistically, GILZ silencing restored ERK phosphorylation and reversed PD-L1 suppression, whereas GILZ overexpression further decreased PD-L1 levels, implicating a GILZ-ERK pathway in the control of PD-L1. These findings uncover a previously unrecognized GR-GILZ-PD-L1 regulatory axis in glioblastoma cells. While these results are based on in vitro models, they provide a rationale for future in vivo studies to determine whether modulation of GILZ may influence immune checkpoint dynamics and therapeutic responsiveness in GBM.
糖皮质激素（GCs），如地塞米松（DEX），常用于胶质母细胞瘤（GBM）患者以控制脑水肿；然而，它们对肿瘤细胞中免疫检查点调节的影响仍未得到充分表征。本研究检测了DEX对U87和U251胶质母细胞瘤细胞系中程序性死亡配体1（PD-L1）和糖皮质激素诱导亮氨酸拉链（GILZ，糖皮质激素受体（GR）信号的下游效应物）表达的影响。DEX在两种模型中均持续诱导GILZ表达，但对PD-L1产生了不同的影响：在U87细胞中抑制，而在U251细胞中上调。在U87细胞中，DEX诱导的PD-L1下调伴随着细胞周期进程加速，提示对肿瘤免疫逃逸和增殖有双重影响。机制上，GILZ沉默恢复了ERK磷酸化并逆转了PD-L1抑制，而GILZ过表达进一步降低了PD-L1水平，提示GILZ-ERK途径参与PD-L1的调控。这些发现揭示了胶质母细胞瘤细胞中一个先前未被认识的GR-GILZ-PD-L1调节轴。虽然这些结果基于体外模型，但它们为未来的体内研究提供了理论依据，以确定GILZ的调节是否可能影响GBM中的免疫检查点动态和治疗反应性。
