Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea.
Department of Nuclear Medicine and Molecular Imaging, Ajou University School of Medicine, Suwon, Republic of Korea.
Lung Cancer. 2019 Mar;129:41-47. doi: 10.1016/j.lungcan.2019.01.004. Epub 2019 Jan 16.
Therapies that target programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) have shown promising efficacy in non-small-cell lung cancer (NSCLC). Hypoxia-related genes are also important regulators of PD-L1, and the role of PD-L1 in NSCLC is still not clear. The objective of this study was to investigate PD-L1 expression and its correlation with hypoxic-inducible factor 1α (HIF1A), vascular endothelial growth factor A (VEGFA), glucose transporter 1 (GLUT1), and carbonic anhydrase 9 (CAIX) expression in NSCLC patients. The association between PD-L1 expression and survival was also determined.
PD-L1/protein expression was evaluated in 295 resected NSCLCs and its correlation with HIF1A, VEGFA, GLUT1, CAIX expression and survival was determined based on immunohistochemical and RNA sequencing data obtained from The Cancer Genome Atlas (TCGA) database.
PD-L1 protein expression was significantly correlated with HIF1A, VEGFA, GLUT1, and CAIX expression only in adenocarcinoma when a 10% or a 50% cut-off was used. PD-L1 mRNA expression was also significantly correlated with HIF1A, VEGFA, GLUT1, and CAIX expression in adenocarcinoma. Univariate analysis revealed that HIF1A expression was associated with poor recurrence-free survival (RFS), and GLUT1 was associated with poor overall survival (OS) and RFS. GLUT1 was an independent prognostic factor for OS in multivariate analysis of immunohistochemical and TCGA data (p = 0.024 and 0.029, respectively). Patients with low expression of both PD-L1 and GLUT1 had longer OS than other patterns in immunohistochemical and TCGA data (p = 0.003 and 0.051, respectively).
PD-L1 protein and mRNA expression were correlated with HIF1A, VEGFA, GLUT1, and CAIX expression in adenocarcinoma alone. Low expression of GLUT1 and low expression of both PD-L1 and GLUT1 were associated with improved prognosis. Our findings support the rationale for co-targeting hypoxia-related genes and PD-L1 in cancer therapy. Expression of hypoxia-related genes may be helpful in selecting patients appropriate for PD-L1 therapy.
针对程序性死亡蛋白-1（PD-1）/程序性死亡配体 1（PD-L1）的治疗方法在非小细胞肺癌（NSCLC）中显示出了有前景的疗效。缺氧相关基因也是 PD-L1 的重要调节因子，但其在 NSCLC 中的作用仍不清楚。本研究旨在探讨 PD-L1 表达及其与缺氧诱导因子 1α（HIF1A）、血管内皮生长因子 A（VEGFA）、葡萄糖转运蛋白 1（GLUT1）和碳酸酐酶 9（CAIX）在 NSCLC 患者中的表达之间的相关性。还确定了 PD-L1 表达与生存之间的关系。
评估了 295 例 NSCLC 切除标本中的 PD-L1/蛋白表达，并基于从癌症基因组图谱（TCGA）数据库获得的免疫组织化学和 RNA 测序数据，确定了其与 HIF1A、VEGFA、GLUT1、CAIX 表达和生存的相关性。
仅在使用 10%或 50%截断值时，PD-L1 蛋白表达与腺癌中的 HIF1A、VEGFA、GLUT1 和 CAIX 表达显著相关。PD-L1 mRNA 表达也与腺癌中的 HIF1A、VEGFA、GLUT1 和 CAIX 表达显著相关。单因素分析显示，HIF1A 表达与无复发生存（RFS）不良相关，GLUT1 与总生存（OS）和 RFS 不良相关。GLUT1 是免疫组织化学和 TCGA 数据多变量分析中 OS 的独立预后因素（p=0.024 和 0.029）。在免疫组织化学和 TCGA 数据中，PD-L1 和 GLUT1 低表达的患者的 OS 均长于其他模式（p=0.003 和 0.051）。
PD-L1 蛋白和 mRNA 表达与腺癌中 HIF1A、VEGFA、GLUT1 和 CAIX 表达相关。GLUT1 低表达和 PD-L1 和 GLUT1 均低表达与预后改善相关。我们的发现支持在癌症治疗中同时靶向缺氧相关基因和 PD-L1 的原理。缺氧相关基因的表达可能有助于选择适合 PD-L1 治疗的患者。
