Division of Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Eur J Immunol. 2010 Dec;40(12):3325-35. doi: 10.1002/eji.201041093.
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.
有许多因素阻碍了癌症的免疫治疗。例如，肿瘤表现出异常的血管系统，似乎形成了对 T 细胞浸润的屏障。另一个主要障碍是由 Treg 造成的。到目前为止，用抗 CD25 抗体常规耗尽 Treg（仅消除 70%的 Treg）未能显著减少已建立的肿瘤的生长。在这里，我们使用 Foxp3.LuciDTR-4 小鼠表明，90-95%的 Treg 耗竭导致大型已建立的肿瘤完全消退，而 70%的耗竭则无效。广泛的 Treg 耗竭诱导了一些对肿瘤排斥至关重要的过程，包括肿瘤特异性 CD8(+)T 细胞的激活和这些细胞进入肿瘤的增强浸润。增强浸润的确切机制尚不清楚，但假设肿瘤血管正常化为浸润提供了帮助。事实上，我们观察到 90%的 Treg 耗竭导致肿瘤血管正常化，表现为渗漏减少和扩张血管数量减少。这些结果表明，对于癌症的临床免疫治疗，最好有能够实现高水平 Treg 耗竭的试剂，这些试剂与疫苗接种等治疗方式结合使用，可能会同时增加 T 细胞的激活和浸润。
