Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer
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Yusuke Inoue1,2, Katsuhiro Yoshimura1,2, Kazutaka Mori2, Nobuya Kurabe1, Tomoaki Kahyo1, Hiroki Mori3, Akikazu Kawase4, Masayuki Tanahashi5, Hiroshi Ogawa6, Naoki Inui2,7, Kazuhito Funai4, Kazuya Shinmura1, Hiroshi Niwa5, Takafumi Suda2, Haruhiko Sugimura1
1Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
2Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
3Department of Pathology, Hamamatsu Medical Center, Hamamatsu, Shizuoka, Japan
4First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
5Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan
6Department of Pathology, Seirei Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan
7Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
Haruhiko Sugimura, email: [email protected]
Keywords: PD-L1, PD-L2, amplification, copy number, non-small-cell lung cancer
Received: November 06, 2015 Accepted: February 24, 2016 Published: April 01, 2016
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.
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