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

keiichi ota, Koichi Azuma, Akihiko Kawahara, Satoshi Hattori, Eiji Iwama, Junko Tanizaki, Taishi Harada, Koichiro Matsumoto, Koichi Takayama, Shinzo Takamori, Masayoshi Kage, Tomoaki Hoshino, Yoichi Nakanishi, Isamu Okamoto

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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 RNA 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.

Original languageEnglish
Pages (from-to)4014-4021
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number17
DOIs
Publication statusPublished - Sep 1 2015

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Oncogene Proteins
Non-Small Cell Lung Carcinoma
Gene Fusion
Phosphatidylinositol 3-Kinases
Cell Line
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Reverse Transcription
Real-Time Polymerase Chain Reaction
Flow Cytometry
Research Design
Up-Regulation
Down-Regulation
RNA
Messenger RNA
Mutation
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Induction of PD-L1 expression by the EML4-ALK oncoprotein and down stream signaling pathways in non-small cell lung cancer. / ota, keiichi; Azuma, Koichi; Kawahara, Akihiko; Hattori, Satoshi; Iwama, Eiji; Tanizaki, Junko; Harada, Taishi; Matsumoto, Koichiro; Takayama, Koichi; Takamori, Shinzo; Kage, Masayoshi; Hoshino, Tomoaki; Nakanishi, Yoichi; Okamoto, Isamu.

In: Clinical Cancer Research, Vol. 21, No. 17, 01.09.2015, p. 4014-4021.

Research output: Contribution to journalArticle

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 2015, 'Induction of PD-L1 expression by the EML4-ALK oncoprotein and down stream signaling pathways in non-small cell lung cancer', Clinical Cancer Research, vol. 21, no. 17, pp. 4014-4021. https://doi.org/10.1158/1078-0432.CCR-15-0016
ota, keiichi ; Azuma, Koichi ; Kawahara, Akihiko ; Hattori, Satoshi ; Iwama, Eiji ; Tanizaki, Junko ; Harada, Taishi ; Matsumoto, Koichiro ; Takayama, Koichi ; Takamori, Shinzo ; Kage, Masayoshi ; Hoshino, Tomoaki ; Nakanishi, Yoichi ; Okamoto, Isamu. / Induction of PD-L1 expression by the EML4-ALK oncoprotein and down stream signaling pathways in non-small cell lung cancer. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 17. pp. 4014-4021.
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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 RNA 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.",
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T1 - Induction of PD-L1 expression by the EML4-ALK oncoprotein and down stream signaling pathways in non-small cell lung cancer

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

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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 RNA 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.

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 RNA 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.

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