ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer
ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer
复制标题
ROS1融合蛋白通过MEK-ERK激活在非小细胞肺癌中诱导PD-L1表达
DOI：
10.1080/2162402x.2020.1758003
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发表时间：
2020-01-01
期刊：
影响因子：
7.2
通讯作者：
Liu, Lunxu
中科院分区：
文献类型：
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作者：
Liu, Zheng;Zhao, Kejia;Liu, Lunxu
摘要引言尽管一些致癌驱动突变与程序性死亡配体1（PD-L1）表达增加相关，但NSCLC细胞中PD-L1表达与ROS 1融合之间的相关性，尤其是对于克唑替尼耐药的NSCLC细胞，尚未完全阐明。材料与方法采用免疫组化（IHC）法检测30例原发性非小细胞肺癌组织中PD-L1的表达。为了评估ROS 1融合与PD-L1表达之间的相关性，我们在ROS 1融合阳性NSCLC细胞系HCC 78中用RNA干扰或特异性抑制剂（克唑替尼）下调ROS 1;或在永生化人支气管上皮细胞系（HBE）中上调ROS 1融合基因。还使用小鼠异种移植物模型来确定ROS 1表达对体内PD-L1表达的影响。生成克唑替尼耐药细胞系，用于测量克唑替尼耐药与PD-L1表达之间的相关性。结果ROS 1基因重排与PD-L1表达上调显著相关。在强制表达ROS 1融合蛋白后，支气管上皮细胞中的PD-L1表达显著上调，并在用克唑替尼处理HCC 78异种移植小鼠模型时消除。我们发现PD-L1的表达在亲代细胞和融合了ROS 1的克唑替尼耐药NSCLC细胞中均受到MEK-ERK通路信号的调节。结论ROS 1融合与PD-L1过表达的相关性提示PD-L1/PD-1阻断剂可作为ROS 1重排伴克唑替尼耐药NSCLC的二线治疗选择。
ABSTRACT Introduction Despite some of the oncogenic driver mutations that have been associated with increased expression of programmed death-ligand 1 (PD-L1), the correlation between PD-L1 expression and ROS1 fusion in NSCLC cells, especially for those with Crizotinib resistance has not been fully addressed. Materials and Methods The expression of PD-L1 in 30 primary NSCLC tumors with/without ROS1-fusion protein was evaluated by immunohistochemical (IHC) analysis. To assess the correlation between ROS1 fusion and PD-L1 expression, we down-regulated ROS1 with RNA interference or specific inhibitor (Crizotinib) in ROS1-fusion positive NSCLC cell line HCC78; or up-regulate ROS1-fusion gene in an immortalized human bronchial epithelial cell line (HBE). Mouse xenograft models were also used to determine the effect of ROS1 expression on PD-L1 expression in vivo. Crizotinib-resistant cell line was generated for measuring the association between Crizotinib resistance and PD-L1 expression. Results ROS1-rearrangement in primary NSCLC tumor was significantly associated with up-regulated PD-L1 expression. PD-L1 expression was significantly up-regulated in bronchial epithelial cells after forced expression of ROS1 fusion and was eliminated when HCC78 xenograft mouse models were treated with Crizotinib. We found PD-L1 expression was modulated by MEK-ERK pathway signaling in both parental and Crizotinib-resistant NSCLC cells with ROS1 fusion. Conclusions The correlation between ROS1-fusion and PD-L1 overexpression suggested that PD-L1/PD-1 blockade could be the second-line treatment option for the Crizotinib-resistant NSCLC with ROS1 rearrangement.