Increased PD-L1 expression in erlotinib-resistant NSCLC cells with MET gene amplification is reversed upon MET-TKI treatment.
Increased PD-L1 expression in erlotinib-resistant NSCLC cells with MET gene amplification is reversed upon MET-TKI treatment.
复制标题
DOI：
10.18632/oncotarget.19920
复制
发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Sørensen BS
中科院分区：
文献类型：
--
作者：
Demuth C;Andersen MN;Jakobsen KR;Madsen AT;Sørensen BS
癌细胞可以通过在细胞表面表达程序性死亡受体1配体（PD-L1）来实现免疫逃避。受体（PD-1）的阻断可以避免这种逃避。在此，我们的目的是研究PD-L1在厄洛替尼耐药肺癌细胞中的表达与MET原癌基因（MET）基因扩增。我们采用了MET基因扩增的厄洛替尼耐药NSCLC细胞系。在MET和丝裂原活化蛋白激酶（MAPK）靶向药物（分别为克唑替尼和SCH 772984）处理后，研究了PD-L1 mRNA（qPCR）和蛋白（流式细胞术）表达。我们证明，在MET基因扩增的厄洛替尼耐药非小细胞肺癌（NSCLC）细胞中，PD-L1表达增加。靶向抑制MET可显著降低PD-L1的基因和蛋白表达。此外，我们证明抑制MAPK也导致PD-L1表达显著降低。总之，这些结果表明，厄洛替尼耐药细胞系中PD-L1的表达与MET活性和下游MAPK途径相关。我们的研究结果表明，在MET基因扩增的厄洛替尼耐药NSCLC细胞中，PD-L1表达增加，并且可以通过靶向抑制MET来避免这种增加。
Cancer cells can achieve immune evasion by expressing the programmed death receptor 1 ligand (PD-L1) on the cell surface. Blockade of the receptor (PD-1) can avert this evasion. Here we aim at investigating PD-L1 expression in erlotinib-resistant lung cancer cells with MET proto-oncogene (MET) gene amplification. We employed an erlotinib-resistant NSCLC cell line with MET gene amplification. PD-L1 mRNA (qPCR) and protein (flow cytometry) expression was investigated after treatment with MET and mitogen-activated protein kinase (MAPK) targeting drugs (crizotinib and SCH772984, respectively). We demonstrate that PD-L1 expression is increased in erlotinib-resistant non-small cell lung cancer (NSCLC) cells with MET gene amplification. Targeted inhibition of MET significantly decreases both gene and protein expression of PD-L1. Further, we demonstrate that inhibiting MAPK also results in a significant decrease in PD-L1 expression. Taken together these results show that expression of PD-L1 in the erlotinib-resistant cell line is associated with MET activity, and the downstream MAPK pathway. Our results demonstrate that PD-L1 expression is increased in erlotinib resistant NSCLC cells with MET gene amplification and that the increase can be averted by targeted inhibition of MET.