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Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non–small cell lung cancer

Date

21 Dec 2015

Session

Melanoma and immunotherapy

Presenters

Keiichi Ota

Citation

Annals of Oncology (2015) 26 (suppl_9): 103-106. 10.1093/annonc/mdv528

Authors

K. Ota1, K. Azuma2, E. Iwama1, T. Harada1, K. Matsumoto1, S. Takamori2, M. Kage2, T. Hoshino2, Y. Nakanishi1, I. Okamoto1

Author affiliations

  • 1 Research Institute For Disease Of The Chest, Kyushu University, 812-8582 - Fukuoka/JP
  • 2 Division Of Respirology, Neurology, And Rheumatology, Department Of Internal Medicine, Kurume University, 830-0011 - Kurume/JP
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Aim/Background

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.

Methods

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 RNA interference with ALK siRNAs. Furthermore, expression of PD-L1 was down-regulated by inhibitors of the MEK-ERK and PI3K-AKT signaling pathways in NSCLC cells positive for either EML4-ALK or activating mutations of the epidermal growth factor receptor (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 up-regulate PD-L1 by activating PI3K-AKT and MEK-ERK signaling pathways in NSCLC reveal a direct link between oncogenic drivers and PD-L1 expression.

Clinical trial identification

Disclosure

All authors have declared no conflicts of interest.

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