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 journalArticlepeer-review

137 Citations (Scopus)


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
Issue number1
Publication statusPublished - 2016

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine


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