EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression
EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression
复制标题
EGFR-TKI 耐药通过增加 PD-L1 表达促进肺癌的免疫逃逸
DOI：
10.1186/s12943-019-1073-4
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发表时间：
2019-11-20
期刊：
影响因子：
37.3
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Peng, Shunli;Wang, Rong;Wang, Wei
背景资料：ATLANTIC试验报告称，肿瘤中PD-L1表达较高与EGFR（+）/ALK（+）非小细胞肺癌（NSCLC）患者的客观缓解较高有关，表明抗PD-1/PD-L1治疗可能作为晚期NSCLC的三线（或更晚）治疗。方法：收集EGFR突变型NSCLC获得性EGFR-TKI耐药前后的TCGA样本和配对NSCLC标本，分析PD-L1、c-MET和HGF的相关性。研究了具有三种已知机制（c-MET扩增、肝细胞生长因子（HGF）和EGFR-T790 M）的EGFR-TKI耐药NSCLC细胞，以确定PD-L1表达状态和免疫逃逸能力。结果：PD-L1、c-MET、HGF三者之间存在正相关关系，PD-L1、c-MET、HGF三者之间存在正相关关系，PD-L1、c-MET、HGF三者之间存在正相关关系。此外，上述三种耐药机制在体外和体内增加了PD-L1表达，减弱了淋巴细胞的活化和细胞毒性，并且PD-L1的下调部分恢复了淋巴细胞的细胞毒性。结论：HGF、MET扩增和EGFR-T790 M通过不同的机制上调NSCLC中PD-L1的表达，促进肿瘤细胞的免疫逃逸。
Background: The ATLANTIC trial reported that higher PD-L1 expression in tumors was involved in a higher objective response in patients with EGFR(+)/ALK(+) non-small cell lung cancer (NSCLC), indicating the possibility of anti-PD-1/PD-L1 therapy as a third-line (or later) treatment for advanced NSCLC. Therefore, the determination of status and regulatory mechanisms of PD-L1 in EGFR mutant NSCLC before and after acquired EGFR-TKIs resistance are meaningful.Methods: The correlation among PD-L1, c-MET, and HGF was analyzed based on TCGA datasheets and paired NSCLC specimens before and after acquired EGFR-TKI resistance. EGFR-TKI resistant NSCLC cells with three well-known mechanisms, c-MET amplification, hepatocyte growth factor (HGF), and EGFR-T790M, were investigated to determinate PD-L1 expression status and immune escape ability. PD-L1-deleted EGFR-TKIs sensitive and resistant cells were used to evaluate the immune escape ability of tumors in mice xenograft models.Results: Positive correlations were found among PD-L1, c-MET, and HGF, based on TCGA datasheets and paired NSCLC specimens. Moreover, the above three resistant mechanisms increased PD-L1 expression and attenuated activation and cytotoxicity of lymphocytes in vitro and in vivo, and downregulation of PD-L1 partially restored the cytotoxicity of lymphocytes. Both MAPK and PI3K pathways were involved in the three types of resistance mechanism-induced PD-L1 overexpression, whereas the NF-kappa B pathway was only involved in T790M-induced PD-L1 expression.Conclusions: HGF, MET-amplification, and EGFR-T790M upregulate PD-L1 expression in NSCLC and promote the immune escape of tumor cells through different mechanisms.