Institute of Neurology (Edinger Institute), Goethe University, Heinrich-Hoffmann-Strasse 7, 60528, Frankfurt, Germany.
Acta Neuropathol. 2011 Sep;122(3):353-65. doi: 10.1007/s00401-011-0858-3. Epub 2011 Jul 21.
Macrophage migration inhibitory factor (MIF), which inhibits apoptosis and promotes angiogenesis, is expressed in cancers suppressing immune surveillance. Its biological role in human glioblastoma is, however, only poorly understood. We examined in-vivo expression of MIF in 166 gliomas and 23 normal control brains by immunohistochemistry. MIF immunoreactivity was enhanced in neoplastic astrocytes in WHO grade II glioma and increased significantly in higher tumour grades (III-IV). MIF expression was further assessed in 12 glioma cell lines in vitro. Quantitative RT-PCR showed that MIF mRNA expression was elevated up to 800-fold in malignant glioma cells compared with normal brain. This translated into high protein levels as assessed by immunoblotting of total cell lysates and by ELISA-based measurement of secreted MIF. Wild-type p53-retaining glioma cell lines expressed higher levels of MIF, which may be connected with the previously described role of MIF as a negative regulator of wild-type p53 signalling in tumour cells. Stable knockdown of MIF by shRNA in glioma cells significantly increased tumour cell susceptibility towards NK cell-mediated cytotoxicity. Furthermore, supernatant from mock-transfected cells, but not from MIF knockdown cells, induced downregulation of the activating immune receptor NKG2D on NK and CD8+ T cells. We thus propose that human glioma cell-derived MIF contributes to the immune escape of malignant gliomas by counteracting NK and cytotoxic T-cell-mediated tumour immune surveillance. Considering its further cell-intrinsic and extrinsic tumour-promoting effects and the availability of small molecule inhibitors, MIF seems to be a promising candidate for future glioma therapy.
巨噬细胞移动抑制因子（MIF）抑制细胞凋亡并促进血管生成，在抑制免疫监视的癌症中表达。然而，其在人类脑胶质瘤中的生物学作用知之甚少。我们通过免疫组化检查了 166 例脑胶质瘤和 23 例正常对照脑组织中 MIF 的体内表达。在 WHO 分级 II 级胶质瘤的肿瘤星形胶质细胞中，MIF 免疫反应性增强，并且在更高的肿瘤分级（III-IV）中显著增加。我们还在体外评估了 12 种脑胶质瘤细胞系中的 MIF 表达。定量 RT-PCR 显示，与正常脑组织相比，恶性胶质瘤细胞中 MIF mRNA 的表达升高了 800 倍。通过免疫印迹检测总细胞裂解物和 ELISA 测量分泌的 MIF，这转化为高蛋白水平。野生型 p53 保留的脑胶质瘤细胞系表达更高水平的 MIF，这可能与 MIF 作为肿瘤细胞中野生型 p53 信号的负调节剂的先前描述的作用有关。通过 shRNA 在脑胶质瘤细胞中稳定敲低 MIF 显著增加了肿瘤细胞对 NK 细胞介导的细胞毒性的敏感性。此外，来自 mock 转染细胞的上清液，但不是来自 MIF 敲低细胞的上清液，诱导 NK 和 CD8+T 细胞上激活免疫受体 NKG2D 的下调。因此，我们提出人类脑胶质瘤细胞衍生的 MIF 通过拮抗 NK 和细胞毒性 T 细胞介导的肿瘤免疫监视，有助于恶性脑胶质瘤的免疫逃逸。鉴于其进一步的细胞内在和外在的肿瘤促进作用以及小分子抑制剂的可用性，MIF 似乎是未来脑胶质瘤治疗的有前途的候选物。
