Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
J Cell Mol Med. 2018 Jun;22(6):3139-3148. doi: 10.1111/jcmm.13593. Epub 2018 Mar 24.
Although tumour PD-L1 (CD274) expression had been used as a predictive biomarker in checkpoint immunotherapy targeting the PD1/PD-L1 axis in various cancers, the regulation of PD-L1 (CD274) expression is unclear. Yes-associated protein (YAP), an important oncogenic protein in Hippo signalling pathway, reportedly promotes cancer development. We investigated whether inhibition of YAP down-regulates PD-L1 (CD274) in human malignant pleural mesothelioma (MPM). Western blotting showed that 2 human MPM cell lines (H2052 and 211H) had increased PD-L1 protein expression compared to H290, MS-1 and H28 cells. In H2052 and 211H cells, PD-L1 mRNA expression was significantly increased compared to other MPM cell lines; YAP knockdown by small interfering RNA decreased PD-L1 protein and mRNA expression. Forced overexpression of the YAP gene increased PD-L1 protein expression in H2452 cells. Chromatin immunoprecipitation (ChIP) assay showed the precipitation of PD-L1 enhancer region encompassing 2 putative YAP-TEAD-binding sites in H2052 cells. We found that, in human MPM tissue microarray samples, YAP and PD-L1 concurrently expressed in immunohistochemistry stain (n = 70, P < .05, chi-square). We conclude that PD-L1 is correlated with YAP expression, and inhibition of YAP down-regulates PD-L1 expression in human MPM. Further study of how YAP regulates PD-L1 in MPM is warranted.
尽管肿瘤 PD-L1（CD274）表达已被用作针对 PD1/PD-L1 轴的各种癌症的检查点免疫治疗的预测性生物标志物，但 PD-L1（CD274）表达的调控尚不清楚。Yes 相关蛋白（YAP）是 Hippo 信号通路中的一种重要致癌蛋白，据报道可促进癌症发展。我们研究了抑制 YAP 是否会下调人类恶性胸膜间皮瘤（MPM）中的 PD-L1（CD274）。Western blot 显示，与 H290、MS-1 和 H28 细胞相比，2 个人类 MPM 细胞系（H2052 和 211H）的 PD-L1 蛋白表达增加。与其他 MPM 细胞系相比，H2052 和 211H 细胞中的 PD-L1 mRNA 表达显著增加；用小干扰 RNA 敲低 YAP 可降低 PD-L1 蛋白和 mRNA 表达。强制过表达 YAP 基因可增加 H2452 细胞中 PD-L1 蛋白的表达。染色质免疫沉淀（ChIP）分析显示，在 H2052 细胞中，PD-L1 增强子区域包含 2 个潜在的 YAP-TEAD 结合位点被沉淀。我们发现，在人类 MPM 组织微阵列样本中，YAP 和 PD-L1 在免疫组化染色中同时表达（n=70，P<0.05，卡方）。我们得出结论，PD-L1 与 YAP 表达相关，抑制 YAP 可下调人类 MPM 中的 PD-L1 表达。进一步研究 YAP 如何调节 MPM 中的 PD-L1 是必要的。
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