351O - Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non–small cell lung cancer

Date 21 December 2015
Event ESMO Asia 2015 Congress
Session Melanoma and immunotherapy
Topics Cancer Immunology and Immunotherapy
Lung and other Thoracic Tumours
Translational Research
Presenter 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
  • 1Research Institute For Disease Of The Chest, Kyushu University, 812-8582 - Fukuoka/JP
  • 2Division Of Respirology, Neurology, And Rheumatology, Department Of Internal Medicine, Kurume University, 830-0011 - Kurume/JP

Abstract

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.