title: Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer.
abstract: New reliable biomarkers are needed to predict the response to immune checkpoint inhibitors against programmed death-1 (PD-1) and its ligand (PD-L1), because PD-L1 expression on tumor cells has limited power for selecting patients who may benefit from such therapy. Here we investigated the significance of PD-L1 and PD-L2 gene copy number gains using fluorescence in situ hybridization as well as PD-L1 and PD-L2 expression in 654 patients with resected non-small-cell lung cancer. The prevalence of PD-L1 amplification and polysomy was 3.1% and 13.2%, respectively. The PD-L1 gene copy number status was in agreement with both the PD-L2 and Janus kinase 2 gene copy number statuses. PD-L1 and PD-L2 expression was observed in 30.7% and 13.1%, respectively. Both PD-L1 copy number gains and expression were associated with smoking-related tumors. Tumor cells with PD-L1 genomic gains exhibited significantly higher levels of PD-L1 expression than those without, but PD-L2 copy number gains were not related to PD-L2 augmentation. PD-L1 gene amplification and polysomy were independently associated with PD-L1 expression, with high immune infiltrates and EGFR expression in a multivariate logistic regression model. Comparative analysis between primary tumors and synchronous regional lymph node metastases revealed that the PD-L1 gene copy number alterations were highly consistent and reproducible compared with the PD-L1 expression. Both PD-L1 amplification and level of protein expression were predictors of poor survival using Cox univariate analyses. Therefore, we conclude that an increase in PD-L1 gene copy number can be a feasible alternative biomarker for predicting response to anti-PD-1/PD-L1 therapy.
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.|Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.|Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Kurabe
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kahyo
authors.affiliation: Department of Pathology, Hamamatsu Medical Center, Hamamatsu, Shizuoka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mori
authors.affiliation: First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Akikazu
authors.initials: A
authors.lastname: Kawase
authors.affiliation: Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tanahashi
authors.affiliation: Department of Pathology, Seirei Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.|Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Inui
authors.affiliation: First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Funai
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shinmura
authors.affiliation: Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Niwa
authors.affiliation: Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sugimura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D056915:DNA Copy Number Variations; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053614:Janus Kinase 2 / Q000235:genetics; D007564:Japan; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010641:Phenotype; D011013:Pneumonectomy; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics*; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; C512478:EGFR protein, human; D066246:ErbB Receptors; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: PD-L1; PD-L2; amplification; copy number; non-small-cell lung cancer