Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non–Small Cell Lung Cancer

Daisuke Shibahara, Kentaro Tanaka, Eiji Iwama, Naoki Kubo, Keiichi Ota, Koichi Azuma, Taishi Harada, Jiro Fujita, Yoichi Nakanishi, Isamu Okamoto

研究成果: ジャーナルへの寄稿記事

5 引用 (Scopus)

抄録

Introduction: The interaction of programmed cell death ligand 2 (PD-L2) with programmed cell death 1 is implicated in tumor immune escape. The regulation of PD-L2 expression in tumor cells has remained unclear, however. We here examined intrinsic and extrinsic regulation of PD-L2 expression in NSCLC. Methods: PD-L2 expression was evaluated by reverse transcription and real-time polymerase chain reaction analysis and by flow cytometry. Results: BEAS-2B cells stably expressing an activated mutant form of EGFR or the echinoderm microtubule associated protein like 4 (EML4)–ALK receptor tyrosine kinase fusion oncoprotein manifested increased expression of PD-L2 at both the mRNA and protein levels. Furthermore, treatment of NSCLC cell lines that harbor such driver oncogenes with corresponding EGFR or ALK tyrosine kinase inhibitors or depletion of EGFR or ALK by small interfering RNA transfection suppressed expression of PD-L2, demonstrating that activating EGFR mutations or echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) fusion intrinsically induce PD-L2 expression. We also found that interferon gamma (IFN-γ) extrinsically induced expression of PD-L2 through signal transducer and activator of transcription 1 signaling in NSCLC cells. Oncogene-driven expression of PD-L2 in NSCLC cells was inhibited by knockdown of the transcription factors signal transducer and activator of transcription 3 (STAT3) or c-FOS. IFN-γ also activated STAT3 and c-FOS, suggesting that these proteins may also contribute to the extrinsic induction of PD-L2 expression. Conclusions: Expression of PD-L2 is induced intrinsically by activating EGFR mutations or EML4-ALK fusion and extrinsically by IFN-γ, with STAT3 and c-FOS possibly contributing to both intrinsic and extrinsic pathways. Our results thus provide insight into the complexity of tumor immune escape in NSCLC.

元の言語英語
ページ(範囲)926-937
ページ数12
ジャーナルJournal of Thoracic Oncology
13
発行部数7
DOI
出版物ステータス出版済み - 7 2018

Fingerprint

Oncogenes
Non-Small Cell Lung Carcinoma
Cell Death
Ligands
STAT3 Transcription Factor
Tumor Escape
Interferon-gamma
STAT1 Transcription Factor
Mutation
Gene Fusion
Oncogene Proteins
Protein-Tyrosine Kinases
Small Interfering RNA
Reverse Transcription
Transfection
Real-Time Polymerase Chain Reaction
Flow Cytometry
Proteins
Transcription Factors
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

これを引用

Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non–Small Cell Lung Cancer. / Shibahara, Daisuke; Tanaka, Kentaro; Iwama, Eiji; Kubo, Naoki; Ota, Keiichi; Azuma, Koichi; Harada, Taishi; Fujita, Jiro; Nakanishi, Yoichi; Okamoto, Isamu.

:: Journal of Thoracic Oncology, 巻 13, 番号 7, 07.2018, p. 926-937.

研究成果: ジャーナルへの寄稿記事

Shibahara, Daisuke ; Tanaka, Kentaro ; Iwama, Eiji ; Kubo, Naoki ; Ota, Keiichi ; Azuma, Koichi ; Harada, Taishi ; Fujita, Jiro ; Nakanishi, Yoichi ; Okamoto, Isamu. / Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non–Small Cell Lung Cancer. :: Journal of Thoracic Oncology. 2018 ; 巻 13, 番号 7. pp. 926-937.
@article{24e99c81ba0844c28028d4d4b9b24d49,
title = "Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non–Small Cell Lung Cancer",
abstract = "Introduction: The interaction of programmed cell death ligand 2 (PD-L2) with programmed cell death 1 is implicated in tumor immune escape. The regulation of PD-L2 expression in tumor cells has remained unclear, however. We here examined intrinsic and extrinsic regulation of PD-L2 expression in NSCLC. Methods: PD-L2 expression was evaluated by reverse transcription and real-time polymerase chain reaction analysis and by flow cytometry. Results: BEAS-2B cells stably expressing an activated mutant form of EGFR or the echinoderm microtubule associated protein like 4 (EML4)–ALK receptor tyrosine kinase fusion oncoprotein manifested increased expression of PD-L2 at both the mRNA and protein levels. Furthermore, treatment of NSCLC cell lines that harbor such driver oncogenes with corresponding EGFR or ALK tyrosine kinase inhibitors or depletion of EGFR or ALK by small interfering RNA transfection suppressed expression of PD-L2, demonstrating that activating EGFR mutations or echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) fusion intrinsically induce PD-L2 expression. We also found that interferon gamma (IFN-γ) extrinsically induced expression of PD-L2 through signal transducer and activator of transcription 1 signaling in NSCLC cells. Oncogene-driven expression of PD-L2 in NSCLC cells was inhibited by knockdown of the transcription factors signal transducer and activator of transcription 3 (STAT3) or c-FOS. IFN-γ also activated STAT3 and c-FOS, suggesting that these proteins may also contribute to the extrinsic induction of PD-L2 expression. Conclusions: Expression of PD-L2 is induced intrinsically by activating EGFR mutations or EML4-ALK fusion and extrinsically by IFN-γ, with STAT3 and c-FOS possibly contributing to both intrinsic and extrinsic pathways. Our results thus provide insight into the complexity of tumor immune escape in NSCLC.",
author = "Daisuke Shibahara and Kentaro Tanaka and Eiji Iwama and Naoki Kubo and Keiichi Ota and Koichi Azuma and Taishi Harada and Jiro Fujita and Yoichi Nakanishi and Isamu Okamoto",
year = "2018",
month = "7",
doi = "10.1016/j.jtho.2018.03.012",
language = "English",
volume = "13",
pages = "926--937",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "7",

}

TY - JOUR

T1 - Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non–Small Cell Lung Cancer

AU - Shibahara, Daisuke

AU - Tanaka, Kentaro

AU - Iwama, Eiji

AU - Kubo, Naoki

AU - Ota, Keiichi

AU - Azuma, Koichi

AU - Harada, Taishi

AU - Fujita, Jiro

AU - Nakanishi, Yoichi

AU - Okamoto, Isamu

PY - 2018/7

Y1 - 2018/7

N2 - Introduction: The interaction of programmed cell death ligand 2 (PD-L2) with programmed cell death 1 is implicated in tumor immune escape. The regulation of PD-L2 expression in tumor cells has remained unclear, however. We here examined intrinsic and extrinsic regulation of PD-L2 expression in NSCLC. Methods: PD-L2 expression was evaluated by reverse transcription and real-time polymerase chain reaction analysis and by flow cytometry. Results: BEAS-2B cells stably expressing an activated mutant form of EGFR or the echinoderm microtubule associated protein like 4 (EML4)–ALK receptor tyrosine kinase fusion oncoprotein manifested increased expression of PD-L2 at both the mRNA and protein levels. Furthermore, treatment of NSCLC cell lines that harbor such driver oncogenes with corresponding EGFR or ALK tyrosine kinase inhibitors or depletion of EGFR or ALK by small interfering RNA transfection suppressed expression of PD-L2, demonstrating that activating EGFR mutations or echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) fusion intrinsically induce PD-L2 expression. We also found that interferon gamma (IFN-γ) extrinsically induced expression of PD-L2 through signal transducer and activator of transcription 1 signaling in NSCLC cells. Oncogene-driven expression of PD-L2 in NSCLC cells was inhibited by knockdown of the transcription factors signal transducer and activator of transcription 3 (STAT3) or c-FOS. IFN-γ also activated STAT3 and c-FOS, suggesting that these proteins may also contribute to the extrinsic induction of PD-L2 expression. Conclusions: Expression of PD-L2 is induced intrinsically by activating EGFR mutations or EML4-ALK fusion and extrinsically by IFN-γ, with STAT3 and c-FOS possibly contributing to both intrinsic and extrinsic pathways. Our results thus provide insight into the complexity of tumor immune escape in NSCLC.

AB - Introduction: The interaction of programmed cell death ligand 2 (PD-L2) with programmed cell death 1 is implicated in tumor immune escape. The regulation of PD-L2 expression in tumor cells has remained unclear, however. We here examined intrinsic and extrinsic regulation of PD-L2 expression in NSCLC. Methods: PD-L2 expression was evaluated by reverse transcription and real-time polymerase chain reaction analysis and by flow cytometry. Results: BEAS-2B cells stably expressing an activated mutant form of EGFR or the echinoderm microtubule associated protein like 4 (EML4)–ALK receptor tyrosine kinase fusion oncoprotein manifested increased expression of PD-L2 at both the mRNA and protein levels. Furthermore, treatment of NSCLC cell lines that harbor such driver oncogenes with corresponding EGFR or ALK tyrosine kinase inhibitors or depletion of EGFR or ALK by small interfering RNA transfection suppressed expression of PD-L2, demonstrating that activating EGFR mutations or echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) fusion intrinsically induce PD-L2 expression. We also found that interferon gamma (IFN-γ) extrinsically induced expression of PD-L2 through signal transducer and activator of transcription 1 signaling in NSCLC cells. Oncogene-driven expression of PD-L2 in NSCLC cells was inhibited by knockdown of the transcription factors signal transducer and activator of transcription 3 (STAT3) or c-FOS. IFN-γ also activated STAT3 and c-FOS, suggesting that these proteins may also contribute to the extrinsic induction of PD-L2 expression. Conclusions: Expression of PD-L2 is induced intrinsically by activating EGFR mutations or EML4-ALK fusion and extrinsically by IFN-γ, with STAT3 and c-FOS possibly contributing to both intrinsic and extrinsic pathways. Our results thus provide insight into the complexity of tumor immune escape in NSCLC.

UR - http://www.scopus.com/inward/record.url?scp=85046154872&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046154872&partnerID=8YFLogxK

U2 - 10.1016/j.jtho.2018.03.012

DO - 10.1016/j.jtho.2018.03.012

M3 - Article

C2 - 29596910

AN - SCOPUS:85046154872

VL - 13

SP - 926

EP - 937

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

SN - 1556-0864

IS - 7

ER -