Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer
Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer
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DOI：
10.1158/1078-0432.ccr-15-0016
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发表时间：
2015-09-01
影响因子：
11.5
通讯作者：
Okamoto, Isamu
中科院分区：
文献类型：
--
作者：
Ota, Keiichi;Azuma, Koichi;Okamoto, Isamu
目的：靶向PD-1和PD-L1介导的免疫检查点的治疗在非小细胞肺癌（NSCLC）患者亚组中显示出抗肿瘤活性。我们现在已经研究了PD-L1的表达及其调控在NSCLC阳性EML 4-ALK融合基因。实验设计：PD-L1在蛋白和mRNA水平的表达在NSCLC细胞系分别通过流式细胞术和逆转录和实时PCR分析。结果：EML 4-ALK阳性的NSCLC细胞株中PD-L1的表达水平高于EML 4-ALK阴性的NSCLC细胞株，EML 4-ALK阳性的NSCLC细胞株中PD-L1的表达水平高于EML 4-ALK阴性的NSCLC细胞株中PD-L1的表达水平。Ba/F3细胞中EML 4-ALK的强制表达显著增加了PD-L1的表达，而EML 4-ALK阳性NSCLC细胞中的内源性PD-L1表达通过特异性ALK抑制剂alectinib或ALK siRNA的RNAi处理而减弱。此外，在EML 4-ALK或EGFR激活突变阳性的NSCLC细胞中，MEK-ERK和PI 3 K-AKT信号通路抑制剂下调PD-L1的表达。结论：NSCLC中EML 4-ALK和突变型EGFR通过激活PI 3 K-AKT和MEK-ERK信号通路上调PD-L1表达，揭示了致癌驱动因子与PD-L1表达之间的直接联系。（C）2015年AACR。
Purpose: Therapies targeted to the immune checkpoint mediated by PD-1 and PD-L1 show antitumor activity in a subset of patients with non-small cell lung cancer (NSCLC). We have now examined PD-L1 expression and its regulation in NSCLC positive for the EML4-ALK fusion gene.Experimental Design: The expression of PD-L1 at the protein and mRNA levels in NSCLC cell lines was examined by flow cytometry and by reverse transcription and real-time PCR analysis, respectively. The expression of PD-L1 in 134 surgically resected NSCLC specimens was evaluated by immunohistochemical analysis.Results: The PD-L1 expression level was higher in NSCLC cell lines positive for EML4-ALK than in those negative for the fusion gene. Forced expression of EML4-ALK in Ba/F3 cells markedly increased PD-L1 expression, whereas endogenous PD-L1 expression in EML4-ALK-positive NSCLC cells was attenuated by treatment with the specific ALK inhibitor alectinib or by RNAi with ALK siRNAs. Furthermore, expression of PD-L1 was downregulated by inhibitors of the MEK-ERK and PI3K-AKT signaling pathways in NSCLC cells positive for either EML4-ALK or activating mutations of the EGFR. Finally, the expression level of PD-L1 was positively associated with the presence of EML4-ALK in NSCLC specimens.Conclusions: Our findings that both EML4-ALK and mutant EGFR upregulate PD-L1 by activating PI3K-AKT and MEK-ERK signaling pathways in NSCLC reveal a direct link between oncogenic drivers and PD-L1 expression. (C)2015 AACR.