Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer.
Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer.
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DOI：
10.18632/oncotarget.8528
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发表时间：
2016-05-31
期刊：
影响因子：
--
通讯作者：
Sugimura H
中科院分区：
文献类型：
--
作者：
Inoue Y;Yoshimura K;Mori K;Kurabe N;Kahyo T;Mori H;Kawase A;Tanahashi M;Ogawa H;Inui N;Funai K;Shinmura K;Niwa H;Suda T;Sugimura H
需要新的可靠的生物标志物来预测免疫检查点抑制剂对程序性死亡-1（PD-1）及其配体（PD-L1）的反应，因为肿瘤细胞上的PD-L1表达对于选择可能受益于这种治疗的患者的能力有限。在这里，我们研究了654例切除的非小细胞肺癌患者中使用荧光原位杂交的PD-L1和PD-L2基因拷贝数增加以及PD-L1和PD-L2表达的意义。PD-L1扩增和多体性的患病率分别为3.1%和13.2%。PD-L1基因拷贝数状态与PD-L2和Janus激酶2基因拷贝数状态一致。分别在30.7%和13.1%的患者中观察到PD-L1和PD-L2表达。PD-L1拷贝数增加和表达均与吸烟相关肿瘤相关。具有PD-L1基因组增益的肿瘤细胞表现出显著高于没有PD-L1基因组增益的肿瘤细胞的PD-L1表达水平，但PD-L2拷贝数增益与PD-L2增强无关。在多变量logistic回归模型中，PD-L1基因扩增和多体性与PD-L1表达、高免疫浸润和EGFR表达独立相关。原发肿瘤和同步区域淋巴结转移之间的比较分析显示，PD-L1基因拷贝数的改变与PD-L1表达相比具有高度一致性和可重复性。使用考克斯单变量分析，PD-L1扩增和蛋白表达水平均为生存不良的预测因子。因此，我们得出结论，PD-L1基因拷贝数的增加可能是预测抗PD-1/PD-L1治疗应答的可行替代生物标志物。
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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影响因子：
30.5
作者：
Latchman, Y;Wood, CR;Freeman, GJ
通讯作者：
Freeman, GJ
影响因子：
20.3
作者：
Green, Michael R.;Monti, Stefano;Shipp, Margaret A.
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Shipp, Margaret A.
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作者：
Fujita, Hiromi;Takayama, Tatsuya;Ozono, Seiichiro
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Ozono, Seiichiro
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10.1
作者：
Mahoney KM;Sun H;Liao X;Hua P;Callea M;Greenfield EA;Hodi FS;Sharpe AH;Signoretti S;Rodig SJ;Freeman GJ
通讯作者：
Freeman GJ
影响因子：
--
作者：
Barrett MT;Anderson KS;Lenkiewicz E;Andreozzi M;Cunliffe HE;Klassen CL;Dueck AC;McCullough AE;Reddy SK;Ramanathan RK;Northfelt DW;Pockaj BA
通讯作者：
Pockaj BA