Biollaz Gregoire, Bernasconi Luca, Cretton Christine, Püntener Ursula, Frei Karl, Fontana Adriano, Suter Tobias
Division of Clinical Immunology, University Hospital of Zurich, Zurich, Switzerland.
Eur J Immunol. 2009 May;39(5):1323-33. doi: 10.1002/eji.200838921.
Gliomas localized within the CNS are generally not rejected by the immune system despite being immunogenic. This failure of the immune system has been associated both with glioma-derived immunosuppressive molecules and the immune-privileged state of the CNS. However, the relative contribution of tumor location to the glioma-mediated immunosuppression, as well as the immune mechanisms involved in the failure of glioma rejection are not fully defined. We report here that syngeneic GL261 gliomas growing either intracranially or subcutaneously in mice are infiltrated by DC and T cells. However, only subcutaneous gliomas elicit an effective anti-tumor immune response. In contrast to DC infiltrating subcutaneously grown GL261 gliomas, tumor-infiltrating DC from intracranial gliomas do not activate antigen-dependent T-cell proliferation in vitro. In addition, brain-localized GL261 gliomas are characterized by significantly higher numbers of Foxp3(+) Treg and higher levels of TGF-beta1 mRNA and protein expression when compared with GL261 gliomas in the skin. Our data show that gliomas in the CNS, but not in the skin, give rise to TGF-beta production and accumulation of both Treg and functionally impaired DC. Thus, not the tumor itself, but its location dictates the efficiency of the anti-tumor immune response.
中枢神经系统内定位的胶质瘤尽管具有免疫原性，但通常不会被免疫系统排斥。免疫系统的这种失效既与胶质瘤衍生的免疫抑制分子有关，也与中枢神经系统的免疫特权状态有关。然而，肿瘤位置对胶质瘤介导的免疫抑制的相对贡献，以及胶质瘤排斥失败所涉及的免疫机制尚未完全明确。我们在此报告，在小鼠颅内或皮下生长的同基因GL261胶质瘤被树突状细胞（DC）和T细胞浸润。然而，只有皮下胶质瘤引发有效的抗肿瘤免疫反应。与浸润皮下生长的GL261胶质瘤的DC不同，来自颅内胶质瘤的肿瘤浸润DC在体外不会激活抗原依赖性T细胞增殖。此外，与皮肤中的GL261胶质瘤相比，脑定位的GL261胶质瘤的特征是Foxp3(+)调节性T细胞（Treg）数量显著增加，TGF-β1 mRNA和蛋白表达水平更高。我们的数据表明，中枢神经系统中的胶质瘤而非皮肤中的胶质瘤会产生TGF-β，并导致Treg和功能受损的DC积累。因此，决定抗肿瘤免疫反应效率的不是肿瘤本身，而是其位置。
