Axl kinase drives immune checkpoint and chemokine signalling pathways in lung adenocarcinomas
Axl kinase drives immune checkpoint and chemokine signalling pathways in lung adenocarcinomas
复制标题
DOI：
10.1186/s12943-019-0953-y
复制
发表时间：
2019-02-11
期刊：
影响因子：
37.3
通讯作者：
Ichinose, Masakazu
中科院分区：
文献类型：
--
作者：
Tsukita, Yoko;Fujino, Naoya;Ichinose, Masakazu
Axl 受体酪氨酸激酶参与生长和转移，是包括肺癌在内的多种癌症预后不良的指标。尽管丝裂原激活蛋白激酶 (MAPK) 途径和上皮间质转化 (EMT) 程序至关重要，但 Axl 驱动的癌症进展的分子机制尚未完全阐明。我们的目的是鉴定肺腺癌中 Axl 激酶上调的分子。通过全局基因表达分析和功能注释聚类，我们发现非小细胞肺癌中AXL表达与免疫检查点分子和趋化因子受体的mRNA表达呈正相关。包括我们生物库在内的验证队列证实，在肺腺癌中，特别是在表皮生长因子受体 (EGFR) 突变阳性腺癌中，AXL 表达与编码程序性死亡配体 1 (PD-L1) 和 CXC 趋化因子受体 6 (CXCR6) 的基因表达显着相关。 Axl 激酶活性的药理学抑制可降低 EGFR 突变阳性细胞系中 PD-L1 和 CXCR6 的 mRNA 表达。我们的数据表明 Axl 激酶作为免疫检查点分子和趋化因子信号通路驱动因素在肺腺癌进展中的新作用。这项研究还强调了临床试验的必要性，以测试 Axl 激酶抑制在 Axl 高表达肺腺癌亚型中的功效。
Axl receptor tyrosine kinase is involved in the growth and metastasis and is an indicator of poor prognosis in several cancers including lung cancers. Although a mitogen-activated protein kinase (MAPK) pathway and an epithelial-to-mesenchymal transition (EMT) program are critical, molecular mechanisms underlying the Axl-driven cancer progression have not been fully elucidated. We aimed to identify molecules up-regulated by Axl kinase in lung adenocarcinomas. Through the global gene expression analysis and the functional annotation clustering, we found that AXL expression positively correlated with mRNA expressions of immune checkpoint molecules and chemokine receptors in non-small-cell lung cancers. Validation cohorts including our biobank confirmed that the AXL expression significantly correlated with expression of genes encoding programmed death-ligand1 (PD-L1) and CXC chemokine receptor 6 (CXCR6) in lung adenocarcinoma, especially in epidermal growth factor receptor (EGFR) mutation-positive adenocarcinoma. Pharmacological inhibition of Axl kinase activity decreased mRNA expressions of PD-L1 and CXCR6 in EGFR mutation-positive cell lines. Our data indicates the novel role of Axl kinase as a driver of immune checkpoint molecules and chemokine signalling pathways in the progression of lung adenocarcinomas. This study also highlights the necessity of clinical trials in order to test the efficacy of Axl kinase inhibition in the Axl-highly expressing subset of lung adenocarcinomas.