Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany. Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
Clin Cancer Res. 2015 Aug 1;21(15):3529-40. doi: 10.1158/1078-0432.CCR-14-2464. Epub 2015 Apr 21.
In recent years, immune therapeutic strategies against non-small cell lung cancer (NSCLC) based on tissue-derived biomarkers, for example PD1/PD-L1 (CD274), have evolved as novel and promising treatment options. However, the crosstalk between tumor and immune cells is poorly understood. Glycodelin (gene name PAEP), initially described in the context of pregnancy and trophoblastic implantation, is a secreted immunosuppressive glycoprotein with an as-of-yet largely unknown function in lung cancer.
In this study, we characterized the expression and role of glycodelin in NSCLC through mRNA and protein expression analyses, functional knockdown experiments, and correlations with clinicopathologic parameters.
Glycodelin mRNA expression was significantly elevated in tumors (n = 336) compared with matched normal tissue (P < 0.0001). Overall survival (OS) was significantly reduced in NSCLC with high glycodelin mRNA levels in women but not in men. Glycodelin was detected in the sera of patients, and the levels correlated with recurrence and metastatic disease. Knockdown of glycodelin with siRNAs in NSCLC cell lines resulted in significant upregulation of immune system modulatory factors such as PDL1, CXCL5, CXCL16, MICA/B, and CD83 as well as proliferation stimulators EDN1 and HBEGF. Furthermore, decreased migration of tumor cells was observed.
Altogether, the comprehensive characterization of glycodelin in NSCLC provides strong support for its use as a biomarker with immune modulatory function.
近年来，基于组织衍生生物标志物（例如 PD1/PD-L1（CD274））的免疫治疗策略已成为治疗非小细胞肺癌（NSCLC）的新的、有前途的治疗选择。然而，肿瘤细胞和免疫细胞之间的相互作用仍知之甚少。糖蛋白 16（基因名称 PAEP）最初在妊娠和滋养层植入的背景下被描述，是一种分泌性免疫抑制糖蛋白，在肺癌中具有尚未完全了解的功能。
在这项研究中，我们通过 mRNA 和蛋白质表达分析、功能敲低实验以及与临床病理参数的相关性，对 NSCLC 中糖蛋白 16 的表达和作用进行了表征。
与匹配的正常组织相比，肿瘤（n=336）中的糖蛋白 16 mRNA 表达显著升高（P<0.0001）。在女性 NSCLC 患者中，高糖蛋白 16 mRNA 水平与总生存期（OS）显著降低相关，但在男性中则没有。在患者的血清中检测到糖蛋白 16，其水平与复发和转移疾病相关。在 NSCLC 细胞系中用 siRNAs 敲低糖蛋白 16 导致免疫系统调节因子如 PD-L1、CXCL5、CXCL16、MICA/B 和 CD83 以及增殖刺激因子 EDN1 和 HBEGF 的显著上调。此外，还观察到肿瘤细胞迁移减少。
总之，对 NSCLC 中糖蛋白 16 的全面表征为其作为具有免疫调节功能的生物标志物的应用提供了有力支持。
