Elimination of regulatory T cells is essential for an effective vaccination with tumor lysate-pulsed dendritic cells in a murine glioma model
Elimination of regulatory T cells is essential for an effective vaccination with tumor lysate-pulsed dendritic cells in a murine glioma model
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DOI：
10.1002/ijc.23284
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发表时间：
2008-04-15
影响因子：
6.4
通讯作者：
Adema, Gosse J.
中科院分区：
文献类型：
--
作者：
Grauer, Oliver M.;Sutmuller, Roger P. M.;Adema, Gosse J.
黑色素瘤和神经胶质瘤细胞都是神经外胚层起源的，并且共享共同的肿瘤相关抗原。在这篇文章中，我们报告说，黑素细胞分化抗原TRP 2（酪氨酸酶相关蛋白2）是不是主要参与肿瘤排斥的同源小鼠胶质瘤。虽然GL 261胶质瘤细胞内源性表达TRP 2并在体外被TRP 2特异性细胞毒性T细胞（CTL）裂解，但用TRP 2肽脉冲的树突状细胞（DC）接种只能在预防性环境中诱导轻微的抗胶质瘤应答，并且在疫苗和肿瘤在同一天施用的严格环境中不能起作用。进一步的分析显示，在调节性T细胞耗尽后，TRP 2不被大量CTL识别，这导致体内肿瘤排斥。与TRP 2肽脉冲的DC相比，肿瘤裂解物脉冲的DC作为疫苗更有效，并且在预防性环境中完全保护小鼠免受肿瘤生长。然而，当肿瘤在同一天接种时，肿瘤裂解物脉冲的DC的疫苗效力不足以防止肿瘤生长。在这种情况下，疫苗接种前Treg耗竭对于增强抗胶质瘤免疫应答至关重要，导致80%的小鼠排斥和长期免疫。因此，我们的结论是，抵消免疫抑制性胶质瘤肿瘤环境通过耗尽调节性T细胞是一个先决条件，成功根除胶质瘤后，通过使用肿瘤裂解物脉冲的DC作为疫苗，在一个更严格的设置多个肿瘤抗原。(c)2007 Wiley-Liss，Inc.
Both melanoma and glioma cells are of neuroectodermal origin and share common tumor associated antigens. In this article, we report that the melanocyte differentiation antigen TRP2 (tyrosinase-related protein 2) is not predominately involved in the tumor rejection of a syngeneic murine glioma. Although GL261 glioma cells endogenously expressed TRP2 and were lysed by TRP2 specific cytotoxic T cells (CTLs) in vitro, vaccinations with TRP2 peptide-pulsed dendritic cells (DCs) could only induce minor antiglioma responses in a prophylactic setting and failed to work in a stringent setting where vaccine and tumor were administered on the same day. Further analysis revealed that TRP2 is not recognized by bulk CTLs after depletion of regulatory T cells which results in tumor rejections in vivo. In contrast to TRP2 peptide-pulsed DC, tumor lysate-pulsed DCs were more potent as a vaccine and completely protected mice from tumor outgrowth in a prophylactic setting. However, the vaccine efficacy of tumor lysate-pulsed DC was not sufficient to prevent the tumor outgrowth when tumors were inoculated the same day. In this case, Treg depletion before vaccination was essential to boost antiglioma immune responses leading to the rejection of 80% of the mice and long-term immunity. Therefore, we conclude that counteracting the immunosuppressive glioma tumor environment via depletion of regulatory T cells is a prerequisite for successful eradication of gliomas after targeting multiple tumor antigens by using tumor lysate-pulsed DCs as a vaccine in a more stringent setting. (c) 2007 Wiley-Liss, Inc.