論文 - 詳細
| RRC ID | 37108 |
|---|---|
| 著者 | Ota K, Azuma K, Kawahara A, Hattori S, Iwama E, Tanizaki J, Harada T, Matsumoto K, Takayama K, Takamori S, Kage M, Hoshino T, Nakanishi Y, Okamoto I. |
| タイトル | Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer. |
| ジャーナル | Clin Cancer Res |
| Abstract |
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. |
| 巻・号 | 21(17) |
| ページ | 4014-21 |
| 公開日 | 2015-9-1 |
| DOI | 10.1158/1078-0432.CCR-15-0016 |
| PII | 1078-0432.CCR-15-0016 |
| PMID | 26019170 |
| MeSH | Anaplastic Lymphoma Kinase B7-H1 Antigen / genetics* Carcinoma, Non-Small-Cell Lung / genetics* Carcinoma, Non-Small-Cell Lung / metabolism* Cell Line, Tumor Cell Membrane / metabolism ErbB Receptors / genetics ErbB Receptors / metabolism Gene Expression Regulation, Neoplastic* Humans Lung Neoplasms / genetics* Lung Neoplasms / metabolism* MAP Kinase Signaling System / drug effects Mutation Oncogene Proteins, Fusion / metabolism* Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins c-akt / antagonists & inhibitors Proto-Oncogene Proteins c-akt / metabolism RNA, Messenger / genetics RNA, Messenger / metabolism Receptor Protein-Tyrosine Kinases / genetics Receptor Protein-Tyrosine Kinases / metabolism Signal Transduction* / drug effects |
| IF | 10.107 |
| 引用数 | 242 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | Ba/F3(RCB0805) |