Efficient Treg depletion induces T-cell infiltration and rejection of large tumors
Efficient Treg depletion induces T-cell infiltration and rejection of large tumors
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DOI：
10.1002/eji.201041093
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发表时间：
2010-12-01
影响因子：
5.4
通讯作者：
Haemmerling, Guenter J.
中科院分区：
文献类型：
--
作者：
Li, Xingrui;Kostareli, Efterpi;Haemmerling, Guenter J.
有许多因素阻碍癌症的免疫治疗。例如，肿瘤表现出异常的脉管系统，其似乎形成针对T细胞浸润的屏障。另一个主要障碍是Treg。到目前为止，用抗CD 25抗体去除Treg的常规方法（仅消除70%的Treg）未能显著降低已建立肿瘤的生长。使用Foxp3.LuciDTR-4小鼠，我们在此表明90-95%的Treg耗竭导致大的已建立肿瘤的完全消退，而70%的耗竭是无效的。广泛的Treg耗竭诱导了许多对肿瘤排斥至关重要的过程，包括肿瘤特异性CD 8（+）T细胞的活化和这些细胞向肿瘤中的浸润增强。增强浸润的确切机制尚不清楚，但假设肿瘤血管系统的正常化有助于浸润。事实上，我们观察到90%的Treg耗竭引起肿瘤血管系统的正常化，如渗漏和扩张血管数量的减少所示。这些结果表明，对于癌症的临床免疫疗法，期望具有允许高水平耗尽Treg的试剂，其与治疗方式如疫苗接种结合，可以伴随增加T细胞活化和浸润。
There are a number of factors that hamper immunotherapy of cancer. For example, tumors exhibit an aberrant vasculature that appears to form a barrier against T-cell infiltration. Another major obstacle is created by Treg. So far, conventional depletion of Treg with anti-CD25 antibodies, which eliminate only 70% of Treg, has failed to significantly reduce the growth of established tumors. Using Foxp3.LuciDTR-4 mice, we show here that 90-95% Treg depletion resulted in complete regression of large established tumors, whereas 70% depletion was ineffective. The extensive Treg depletion induced a number of processes that are critical for tumor rejection, including activation of tumor-specific CD8(+) T cells and enhanced infiltration of these cells into the tumor. The precise mechanism of enhanced infiltration is not known, but normalization of the tumor vasculature is assumed to assist infiltration. Indeed, we observed that 90% Treg depletion caused normalization of the tumor vasculature as indicated by a reduction in leakiness and the number of dilated vessels. These results suggest that for clinical immunotherapy of cancer, it would be desirable to have reagents that allow high-level depletion of Treg, which, in conjunction with treatment modalities such as vaccination, may concomitantly increase T-cell activation and infiltration.