Asbestos Diseases Research Institute, Sydney, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia.
Asbestos Diseases Research Institute, Sydney, Australia.
J Thorac Oncol. 2017 Sep;12(9):1421-1433. doi: 10.1016/j.jtho.2017.05.024. Epub 2017 Jun 16.
INTRODUCTION: The upregulation of programmed death ligand 1 (PD-L1) is found in many cancers and contributes to evasion of the host's immune defense. In malignant pleural mesothelioma (MPM), PD-L1 expression is associated with the nonepithelioid histological subtype and poor prognosis, but the pathways involved in control of PD-L1 expression in MPM are poorly understood. To address one possible means of PD-L1 regulation we investigated the relationship between dysregulated microRNA levels and PD-L1 expression. METHODS: PD-L1 expression was analyzed by immunohistochemistry in tissue microarrays prepared from samples from patients undergoing an operation (pleurectomy with or without decortication). MicroRNA expression was analyzed by reverse-transcriptase quantitative polymerase chain reaction. Regulation of PD-L1 expression in cell lines was assessed after transfection with microRNA mimics and small interfering RNAs. Interaction between microRNAs and PD-L1 was analyzed by using argonaute-2 immunoprecipitation and a luciferase reporter assay. RESULTS: In a series of 72 patients with MPM, 18 (25%) had positive PD-L1 staining, and this was more common in patients with the nonepithelioid subtype (p = 0.01). PD-L1 expression was associated with poor survival (median overall survival 4.0 versus 9.2 months with positive versus negative PD-L1 expression [p < 0.001]), and in multivariate analyses, PD-L1 expression remained a significant adverse prognostic indicator (hazard ratio = 2.2, 95% confidence interval: 1.2-4.1, p < 0.01). In the same patient series, PD-L1 expression was also associated with downregulation of microRNAs previously shown to have tumor suppressor activity in MPM. The median microRNA expression levels of miR-15b, miR-16, miR-193a-3p, miR-195, and miR-200c were significantly lower in the PD-L1-positive samples. Transfecting MPM cell lines with mimics corresponding to miR-15a and miR-16, both of which are predicted to target PD-L1, led to downregulation of PD-L1 mRNA and protein. In addition, miR-193a-3p, with an alternative G-U-containing target site, also caused PD-L1 downregulation. CONCLUSIONS: Together, these data suggest that tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in MPM.
简介：程序性死亡配体 1（PD-L1）的上调存在于许多癌症中，并有助于逃避宿主的免疫防御。在恶性胸膜间皮瘤（MPM）中，PD-L1 的表达与非上皮样组织学亚型和预后不良有关，但控制 MPM 中 PD-L1 表达的途径知之甚少。为了研究 PD-L1 调节的一种可能途径，我们研究了失调的 microRNA 水平与 PD-L1 表达之间的关系。
方法：通过免疫组织化学分析组织微阵列中患者手术（胸膜切除术加或不加剥脱术）样本中的 PD-L1 表达。通过逆转录酶定量聚合酶链反应分析 microRNA 表达。通过转染 microRNA 模拟物和小干扰 RNA 评估细胞系中 PD-L1 表达的调节。通过使用 Argonaute-2 免疫沉淀和荧光素酶报告基因测定分析 microRNA 和 PD-L1 之间的相互作用。
结果：在一系列 72 名 MPM 患者中，有 18 名（25%）患者 PD-L1 染色阳性，无上皮样亚型患者更常见（p=0.01）。PD-L1 表达与生存不良相关（总生存中位数 4.0 个月与 PD-L1 阳性与阴性表达[ p<0.001]），多变量分析中，PD-L1 表达仍然是一个显著的预后不良指标（危险比=2.2，95%置信区间：1.2-4.1，p<0.01）。在同一患者系列中，PD-L1 表达也与先前在 MPM 中具有肿瘤抑制活性的 microRNAs 的下调有关。miR-15b、miR-16、miR-193a-3p、miR-195 和 miR-200c 的中位 microRNA 表达水平在 PD-L1 阳性样本中明显较低。用模拟物转染 MPM 细胞系，模拟物对应的 miR-15a 和 miR-16，都被预测为靶向 PD-L1，导致 PD-L1 mRNA 和蛋白下调。此外，miR-193a-3p 具有替代的 G-U 富含靶位点，也导致 PD-L1 下调。
结论：综上所述，这些数据表明肿瘤抑制 microRNAs 有助于调节 MPM 中 PD-L1 的表达。
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