Roth W, Isenmann S, Nakamura M, Platten M, Wick W, Kleihues P, Bähr M, Ohgaki H, Ashkenazi A, Weller M
Laboratories of Molecular Neuro-Oncology, University of Tübingen, School of Medicine, Germany.
Cancer Res. 2001 Mar 15;61(6):2759-65.
Decoy receptor 3 (DcR3) is a newly identified soluble protein that binds to CD95 ligand (CD95L) and inhibits its proapoptotic activity. Here we report that DcR3 is expressed by the majority of long-term and ex vivo malignant glioma cell lines as well as in human glioblastoma in vivo. Expression of DcR3 correlates with the grade of malignancy: 15 of 18 (83%) glioblastomas (WHO grade IV) but none of 11 diffuse astrocytomas (WHO grade II) exhibited DcR3 immunoreactivity. We also demonstrate that human malignant glioma cells engineered to release high amounts of DcR3 into the cell culture supernatant are protected from CD95L-induced apoptotic cell death. In contrast, DcR3 does not confer protection from the death ligand Apo2 ligand (TRAIL). Importantly, ectopic expression of DcR3 resulted in substantial differences in immune cell infiltration in the 9L rat gliosarcoma model. Thus, the infiltration of CD4+ and CD8+ T cells as well as microglia/macrophages into glioma was substantially decreased in DcR3-producing tumors compared with control tumors. Chemotaxis assays revealed that DcR3 counteracts the chemotactic activity of CD95L against microglial cells in vitro. These findings suggest that DcR3 may be involved in the progression and immune evasion of malignant gliomas.
诱饵受体3（DcR3）是一种新发现的可溶性蛋白，它能与CD95配体（CD95L）结合并抑制其促凋亡活性。在此我们报告，大多数长期培养的和体外培养的恶性胶质瘤细胞系以及体内的人类胶质母细胞瘤中均表达DcR3。DcR3的表达与恶性程度相关：18例胶质母细胞瘤（世界卫生组织IV级）中有15例（83%）呈现DcR3免疫反应性，而11例弥漫性星形细胞瘤（世界卫生组织II级）均未呈现。我们还证明，经基因工程改造后能向细胞培养上清液中释放大量DcR3的人类恶性胶质瘤细胞可免受CD95L诱导的凋亡性细胞死亡。相反，DcR3不能使细胞免受死亡配体Apo2配体（TRAIL）的影响。重要的是，在9L大鼠胶质肉瘤模型中，DcR3的异位表达导致免疫细胞浸润出现显著差异。因此，与对照肿瘤相比，产生DcR3的肿瘤中CD4+和CD8+ T细胞以及小胶质细胞/巨噬细胞向胶质瘤中的浸润显著减少。趋化性分析显示，DcR3在体外可抵消CD95L对小胶质细胞的趋化活性。这些发现表明，DcR3可能参与恶性胶质瘤的进展和免疫逃逸。
