PT  - JOURNAL ARTICLE
AU  - Ota, Keiichi
AU  - Azuma, Koichi
AU  - Kawahara, Akihiko
AU  - Hattori, Satoshi
AU  - Iwama, Eiji
AU  - Tanizaki, Junko
AU  - Harada, Taishi
AU  - Matsumoto, Koichiro
AU  - Takayama, Koichi
AU  - Takamori, Shinzo
AU  - Kage, Masayoshi
AU  - Hoshino, Tomoaki
AU  - Nakanishi, Yoichi
AU  - Okamoto, Isamu
TI  - Induction of PD-L1 Expression by the EML4–ALK Oncoprotein and Downstream Signaling Pathways in Non–Small Cell Lung Cancer
AID  - 10.1158/1078-0432.CCR-15-0016
DP  - 2015 Sep 01
TA  - Clinical Cancer Research
PG  - 4014--4021
VI  - 21
IP  - 17
4099  - http://clincancerres.aacrjournals.org/content/21/17/4014.short
4100  - http://clincancerres.aacrjournals.org/content/21/17/4014.full
SO  - Clin Cancer Res2015 Sep 01; 21
AB  - 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. Clin Cancer Res; 21(17); 4014–21. ©2015 AACR.