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Clin Cancer Res. 2015 Sep 1;21(17):4014-21. doi: 10.1158/1078-0432.CCR-15-0016. Epub 2015 May 27.

Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer.

Author information

1
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
2
Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan.
3
Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan.
4
Biostatistics Center, Kurume University, Fukuoka, Japan.
5
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
6
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
7
Department of Surgery, Kurume University School of Medicine, Fukuoka, Japan.
8
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan.
9
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan. okamotoi@kokyu.med.kyushu-u.ac.jp.

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.

PMID:
26019170
DOI:
10.1158/1078-0432.CCR-15-0016
[Indexed for MEDLINE]
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