PD-L1 is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer

Seiichi Ikeda, Tatsuro Okamoto, Shinji Okano, Yuichiro Umemoto, Tetsuzo Tagawa, Yosuke Morodomi, Mikihiro Kohno, Shinichiro Shimamatsu, Hirokazu Kitahara, Yuzo Suzuki, Takatoshi Fujishita, Yoshihiko Maehara

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Objectives: The programmed death ligand 1(PD-L1)/programmed cell death protein 1 (PD-1) pathway is one of the most important checkpoint pathways for mediating tumorinduced immune suppression through T-cell exhaustion. Recently, targeted therapies using monoclonal antibodies against components of this pathway have been shown to reduce tumor burden in patients with non-small cell lung cancer (NSCLC). However, the prognostic significance of PDL1 expression is controversial and the precise mechanisms of PD-L1 gene activation in lung cancer have yet to be clarified. Methods: We investigated copy number alterations (CNAs) in the PD-L1 gene by real-time PCR in 94 surgically resected lung cancer samples to find possible associations between PD-L1 CNA and lung cancer biology. Janus kinase 2 gene (JAK2) CNA and its influence on the PD-L1/PD-1 pathway were also assessed. Results: Five samples were shown to have PD-L1 gene amplification, whereas 89 samples did not. The patients with PD-L1 amplification had worse prognoses than did those without PD-L1 amplification. Genetic amplification of the PD-L1 gene was correlated with JAK2 gene amplification. The lung cancer cell line HCC4006 was found to harbor both JAK2 and PD-L1 amplification. Flow cytometry analyses revealed the level of PD-L1 protein expression to be higher in HCC4006 cells than in other NSCLC cell lines. Expression of the PD-L1 protein was significantly reduced by the JAK2 inhibitor TG-101348 and the signal transducer and activator of transcription 3 (STAT-3) inhibitor BP-1-102, but not by the STAT1 inhibitor fludarabine. Conclusions: Our data suggest that expression of PD-L1 protein is upregulated by the simultaneous amplification of the PD-L1 and JAK2 genes through JAK-STAT signaling in NCSLC.

Original languageEnglish
Pages (from-to)62-71
Number of pages10
JournalJournal of Thoracic Oncology
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

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Janus Kinase 2
Non-Small Cell Lung Carcinoma
Ligands
Genes
Lung Neoplasms
Gene Amplification
CD274 Antigen
Cell Line
STAT3 Transcription Factor
Proteins
Gene Dosage
Tumor Burden

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

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PD-L1 is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer. / Ikeda, Seiichi; Okamoto, Tatsuro; Okano, Shinji; Umemoto, Yuichiro; Tagawa, Tetsuzo; Morodomi, Yosuke; Kohno, Mikihiro; Shimamatsu, Shinichiro; Kitahara, Hirokazu; Suzuki, Yuzo; Fujishita, Takatoshi; Maehara, Yoshihiko.

In: Journal of Thoracic Oncology, Vol. 11, No. 1, 01.01.2016, p. 62-71.

Research output: Contribution to journalArticle

Ikeda, S, Okamoto, T, Okano, S, Umemoto, Y, Tagawa, T, Morodomi, Y, Kohno, M, Shimamatsu, S, Kitahara, H, Suzuki, Y, Fujishita, T & Maehara, Y 2016, 'PD-L1 is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer', Journal of Thoracic Oncology, vol. 11, no. 1, pp. 62-71. https://doi.org/10.1016/j.jtho.2015.09.010
Ikeda, Seiichi ; Okamoto, Tatsuro ; Okano, Shinji ; Umemoto, Yuichiro ; Tagawa, Tetsuzo ; Morodomi, Yosuke ; Kohno, Mikihiro ; Shimamatsu, Shinichiro ; Kitahara, Hirokazu ; Suzuki, Yuzo ; Fujishita, Takatoshi ; Maehara, Yoshihiko. / PD-L1 is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer. In: Journal of Thoracic Oncology. 2016 ; Vol. 11, No. 1. pp. 62-71.
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abstract = "Objectives: The programmed death ligand 1(PD-L1)/programmed cell death protein 1 (PD-1) pathway is one of the most important checkpoint pathways for mediating tumorinduced immune suppression through T-cell exhaustion. Recently, targeted therapies using monoclonal antibodies against components of this pathway have been shown to reduce tumor burden in patients with non-small cell lung cancer (NSCLC). However, the prognostic significance of PDL1 expression is controversial and the precise mechanisms of PD-L1 gene activation in lung cancer have yet to be clarified. Methods: We investigated copy number alterations (CNAs) in the PD-L1 gene by real-time PCR in 94 surgically resected lung cancer samples to find possible associations between PD-L1 CNA and lung cancer biology. Janus kinase 2 gene (JAK2) CNA and its influence on the PD-L1/PD-1 pathway were also assessed. Results: Five samples were shown to have PD-L1 gene amplification, whereas 89 samples did not. The patients with PD-L1 amplification had worse prognoses than did those without PD-L1 amplification. Genetic amplification of the PD-L1 gene was correlated with JAK2 gene amplification. The lung cancer cell line HCC4006 was found to harbor both JAK2 and PD-L1 amplification. Flow cytometry analyses revealed the level of PD-L1 protein expression to be higher in HCC4006 cells than in other NSCLC cell lines. Expression of the PD-L1 protein was significantly reduced by the JAK2 inhibitor TG-101348 and the signal transducer and activator of transcription 3 (STAT-3) inhibitor BP-1-102, but not by the STAT1 inhibitor fludarabine. Conclusions: Our data suggest that expression of PD-L1 protein is upregulated by the simultaneous amplification of the PD-L1 and JAK2 genes through JAK-STAT signaling in NCSLC.",
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AU - Okamoto, Tatsuro

AU - Okano, Shinji

AU - Umemoto, Yuichiro

AU - Tagawa, Tetsuzo

AU - Morodomi, Yosuke

AU - Kohno, Mikihiro

AU - Shimamatsu, Shinichiro

AU - Kitahara, Hirokazu

AU - Suzuki, Yuzo

AU - Fujishita, Takatoshi

AU - Maehara, Yoshihiko

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