Journal Article

Axl kinase drives immune checkpoint and chemokine signalling pathways in lung adenocarcinomas

Fujino, Naoya, Okada, Yoshinori, Kyogoku, Yorihiko, Ichinose, Masakazu, Yamada, Mitsuhiro, Saito, Ryoko, Sugiura, Hisatoshi, Tsukita, Yoko, Okazaki, Tatsuma, Inoue, Akira, Fujishima, Fumiyoshi, Okutomo, Koji, Miyauchi, Eisaku, Itakura, Koji

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenocarcinoma / Adenocarcinoma of Lung - genetics / Adenocarcinoma of Lung - immunology / Adenocarcinoma of Lung - pathology / Analysis / Antigens / Antineoplastic Agents - pharmacology / Apoptosis / Axl protein / Axl receptor tyrosine kinase / B7-H1 Antigen - genetics / B7-H1 Antigen - immunology / Benzocycloheptenes - pharmacology / Biochemistry / Biomedical and Life Sciences / Biomedicine / Cancer metastasis / Cancer Research / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - immunology / Carcinoma, Non-Small-Cell Lung - pathology / Cell Line, Tumor / Chemokine receptors / Chemokine signalling / Chemokines / Clinical trials / Cohort Studies / CXC chemokines / Development and progression / Disease Progression / Epidermal growth factor / Epidermal growth factor receptors / Epidermal growth factors / Epithelial-Mesenchymal Transition - drug effects / Epithelial-Mesenchymal Transition - genetics / Epithelial-Mesenchymal Transition - immunology / ErbB Receptors - genetics / ErbB Receptors - immunology / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Genes / Genetic research / Global gene expression array / Humans / Immune checkpoint / Immune checkpoint molecules / Kinases / Letter to the Editor / Ligands / Lung cancer / Lung Neoplasms - genetics / Lung Neoplasms - immunology / Lung Neoplasms - pathology / Lungs / MAP kinase / Medical prognosis / Medical research / Medical schools / Medicine / Mesenchyme / Messenger RNA / Metastases / Metastasis / Mitogens / Molecular modelling / Mutation / Nivolumab / Non-small cell lung cancer / Oligonucleotide Array Sequence Analysis / Oncology / Ontology / Ovarian cancer / PD-L1 protein / Phenols (Class of compounds) / Phosphorylation / Prognosis / Protein Kinase Inhibitors - pharmacology / Protein kinases / Protein-tyrosine kinase receptors / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - immunology / Receptor Protein-Tyrosine Kinases - genetics / Receptor Protein-Tyrosine Kinases - immunology / Receptors, CXCR6 - genetics / Receptors, CXCR6 - immunology / RNA / RNA, Messenger - genetics / RNA, Messenger - immunology / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Signal transduction / Signal Transduction - genetics / Signal Transduction - immunology / Stem cells / Thoracic surgery / Triazoles - pharmacology / Tyrosine