Department of Biological Sciences, St. John's University, New York 11439, USA.
Department of Biological Sciences, St. John's University, New York 11439, USA.
Cell Signal. 2022 Sep;97:110400. doi: 10.1016/j.cellsig.2022.110400. Epub 2022 Jul 9.
Expression of the immune checkpoint programmed death ligand-1 (PD-L1) is increased in ovarian cancer (OC) and correlates with poor prognosis. Interferon-γ (IFNγ) induces PD-L1 expression in OC cells, resulting in their increased proliferation and tumor growth, but the mechanisms that regulate the PD-L1 expression in OC remain unclear. Here, we show that the IFNγ-induced PD-L1 expression in OC cells is associated with increased levels of STAT1, Tyr-701 pSTAT1 and Ser-727 pSTAT1. Suppression of JAK1 and STAT1 significantly decreases the IFNγ-induced PD-L1 expression in OC cells, and STAT1 overexpression increases the IFNγ-induced PD-L1 expression. In addition, IFNγ induces expression of the transcription factor interferon regulatory factor 1 (IRF1) and IRF1 suppression attenuates the IFNγ-induced gene and protein levels of PD-L1. Chromatin immunoprecipitation results show that IFNγ induces PD-L1 promoter acetylation and recruitment of STAT1, Ser-727 pSTAT1 and IRF1 in OC cells. Together, these findings demonstrate that the IFNγ-induced PD-L1 expression in OC cells is regulated by JAK1, STAT1, and IRF1 signaling, and suggest that targeting the JAK1/ STAT1/IRF1 pathway may provide a leverage to regulate the PD-L1 levels in ovarian cancer.
免疫检查点程序性死亡配体 1（PD-L1）在卵巢癌（OC）中的表达增加，并与预后不良相关。干扰素-γ（IFNγ）可诱导 OC 细胞中 PD-L1 的表达，导致其增殖和肿瘤生长增加，但调节 OC 中 PD-L1 表达的机制尚不清楚。在这里，我们表明 IFNγ 诱导的 OC 细胞中 PD-L1 的表达与 STAT1、Tyr-701 pSTAT1 和 Ser-727 pSTAT1 水平的增加有关。抑制 JAK1 和 STAT1 可显著降低 OC 细胞中 IFNγ 诱导的 PD-L1 表达，而过表达 STAT1 则增加 IFNγ 诱导的 PD-L1 表达。此外，IFNγ 诱导转录因子干扰素调节因子 1（IRF1）的表达，而 IRF1 的抑制可减弱 IFNγ 诱导的 PD-L1 基因和蛋白水平。染色质免疫沉淀结果表明，IFNγ 可诱导 OC 细胞中 PD-L1 启动子乙酰化以及 STAT1、Ser-727 pSTAT1 和 IRF1 的募集。综上所述，这些发现表明，IFNγ 诱导的 OC 细胞中 PD-L1 的表达受 JAK1、STAT1 和 IRF1 信号通路的调节，并提示靶向 JAK1/STAT1/IRF1 通路可能为调节卵巢癌中 PD-L1 水平提供了一种手段。
