CD4+FoxP3+regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo
CD4+FoxP3+regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo
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DOI：
10.1002/ijc.22607
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发表时间：
2007-07-01
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.;Nierkens, Stefan;Adema, Gosse J.
调节性T细胞(Treg)的抑制活性被认为是限制免疫介导的肿瘤细胞破坏的重要因素。然而，人们对Treg在肿瘤中的存在和功能知之甚少。在这里，我们展示了在同基因的小鼠脑胶质瘤模型中，脑瘤中的CD4+FoxP3+Treg随时间的积累。进一步分析发现，在肿瘤生长过程中，CD25、CTLA-4、GITR和CXCR4对肿瘤内CD4+FoxP3+Treg的上调具有时间依赖性。此外，新分离的肿瘤内Treg在直接体外测试时具有高度的抑制作用。用抗CD25单抗(MAbs)治疗后，生长中的肿瘤中这些高度抑制的CD4+FoxP3+细胞的数量显著减少，并引发了对CD4和CD8T细胞的依赖破坏。Treg的去除与阻断CTLA-4单抗的应用相结合，进一步提高了胶质瘤特异性的CD4+和CD8+效应T细胞以及抗胶质瘤IgG2a抗体的滴度，导致肿瘤完全根除，没有任何自身免疫的迹象。这些数据表明，肿瘤内CD4+FoxP3+Treg的积聚和激活是胶质瘤的主要免疫逃逸机制，并强调了控制肿瘤浸润性Treg在胶质瘤免疫治疗中的重要性。(C)2007年Wiley-Liss，Inc.
The suppressive activity of regulatory T cells (Treg) has been implicated as an important factor limiting immune mediated destruction of tumor cells. However, not much is known about the presence and function of Treg within tumors. Here we show in a syngeneic murine glioma model a time-dependent accumulation of CD4+FoxP3+ Treg in brain tumors. Further analysis revealed a time-dependent upregulation of CD25, CTLA-4, GITR and CXCR4 on intratumoral CD4+FoxP3+ Treg during tumor growth. Moreover, freshly isolated intratumoral Treg were highly suppressive when tested directly ex vivo. Treatment with anti-CD25 monoclonal antibodies (mAbs) significantly reduced the number of these highly suppressive CD4+FoxP3+ cells within the growing tumor and provoked a CD4 and CD8 T cell dependent destruction of the glioma cells. Combining Treg depletion with administration of blocking CTLA-4 mAbs further boosted glioma-specific CD4+ and CD8+ effector T cells as well as antiglioma IgG2a antibody titers resulting in complete tumor eradication without any signs of autoimmunity. These data illustrate that intratumoral accumulation and activation of CD4+FoxP3+ Treg act as a dominant immune escape mechanism for gliomas and underline the importance of controlling tumor- infiltrating Treg in glioma immunotherapy. (C) 2007 Wiley-Liss, Inc.