title: PD-L1 Is Upregulated by Simultaneous Amplification of the PD-L1 and JAK2 Genes in Non-Small Cell Lung Cancer.
abstract: OBJECTIVE
  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 tumor-induced 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 PD-L1 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.
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: tatsuro@surg2.med.kyushu-u.ac.jp.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Okano
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Umemoto
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Tetsuzo
authors.initials: T
authors.lastname: Tagawa
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Morodomi
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Kohno
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Shimamatsu
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kitahara
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Fujishita
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Gene amplification; Inhibitor; JAK2; Non–small cell lung cancer; PD-L1