CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative
CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative
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DOI：
10.1002/eji.200324181
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发表时间：
2004-02-01
影响因子：
5.4
通讯作者：
Martin, F
中科院分区：
文献类型：
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作者：
Ghiringhelli, F;Larmonier, N;Martin, F
我们通过比较从大鼠结肠癌分离的免疫原性和耐受性肿瘤细胞克隆，探讨了肿瘤提高免疫耐受性的机制。当注射到同基因宿主中时，免疫原性的REGb细胞产生被排斥的肿瘤，而耐受的PROB细胞产生进展的肿瘤并抑制REGb肿瘤的消退。我们在这里表明，探测肿瘤的体积与淋巴组织中CD4(+)CD25(+)调节性T淋巴细胞的扩张有关。这些细胞在体内延迟REGb肿瘤的排斥反应，并在体外抑制T细胞介导的针对REGb细胞的免疫反应，其机制需要效应者和调节性T细胞之间的细胞接触，并涉及转化生长因子-β。虽然PROB荷瘤大鼠的总T细胞没有产生明显的抗肿瘤免疫反应，但CD25(+)T细胞的耗尽可以恢复这种反应。单次给药环磷酰胺会耗尽PROB肿瘤动物体内的CD4(+)CD25(+)T细胞，延缓PROB肿瘤的生长，并治愈已建立的PROB肿瘤的大鼠，然后进行免疫治疗，但单独使用时没有疗效。这些结果证明了CD4(+)CD25(+)调节性T细胞在肿瘤诱导的免疫耐受中的作用，以及调节性T细胞耗竭使已建立的肿瘤对免疫治疗敏感的兴趣。
We investigated the mechanisms of immune tolerance raised by tumors by comparing immunogenic and tolerogenic tumor cell clones isolated from a rat colon carcinoma. When injected into syngeneic hosts, the immunogenic REGb cells yield tumors that are rejected, while the tolerogenic PROb cells yield progressive tumors and inhibit the regression of REGb tumors. We show here that PROb tumor volume is correlated with an expansion of CD4(+)CD25(+) regulatory T lymphocytes in lymphoid tissues. These cells delay in vivo the rejection of REGb tumors and inhibit in vitro T cell-mediated immune responses against REGb cells through a mechanism that requires cell contact between effector and regulatory T cells and involves TGF-beta. While total T cells from PROb tumor-bearing rats yield no apparent anti-tumor immune response, depletion of CD25(+) T cells restores this reactivity. A single administration of cyclophosphamide depletes CD4(+)CD25(+) T cells in PROb tumor-bearing animals, delays the growth of PROb tumors, and cures rats bearing established PROb tumors when followed by an immunotherapy which has no curative effect when administered alone. These results demonstrate the role of CD4(+)CD25(+) regulatory T cells in tumor-induced immune tolerance and the interest of regulatory T cell depletion to sensitize established tumors to immunotherapy.