Modulation of protective T cell immunity by complement inhibitor expression on tumor cells
Modulation of protective T cell immunity by complement inhibitor expression on tumor cells
复制标题
DOI：
10.1158/0008-5472.can-08-0502
复制
发表时间：
2008-08-15
期刊：
影响因子：
11.2
通讯作者：
Tomlinson, Stephen
中科院分区：
文献类型：
--
作者：
Varela, Juan C.;Imai, Masaki;Tomlinson, Stephen
在癌细胞上表达的补体抑制蛋白可以提供抗肿瘤抗体的保护，并且可能潜在地调节对肿瘤相关抗原的免疫应答的诱导。在目前的研究中，我们研究了补体抑制剂下调对免疫应答的效应期和诱导期的影响。稳定的小干扰RNA介导的补体抑制剂Crry对MB 49小鼠膀胱癌细胞的下调增加了它们对单克隆抗体和补体的体外敏感性。在转移性癌症的同基因模型中，Cry在i. v. -注射的MB 49细胞与肿瘤负荷的显著降低和受攻击小鼠存活率的增加相关。然而，单克隆抗体治疗没有额外的好处。存在抗肿瘤IgG应答，但该应答不受接种的肿瘤细胞上Crry下调的影响。MB 49细胞上Crry的下调导致激发小鼠中增强的抗肿瘤T细胞应答（通过淋巴细胞IFN-γ分泌测量），并且在注射MB 49细胞之前小鼠的CD 8 + T细胞消耗完全消除了Crry下调对肿瘤负荷和存活的影响。C3的缺乏也消除了Crry下调对MB 49攻击小鼠的存活的影响，表明补体依赖性机制。这些数据表明，在肿瘤细胞上表达的补体抑制剂可以抑制T细胞应答，并且增强肿瘤细胞表面上的补体活化可以促进保护性T细胞免疫。
Complement-inhibitory proteins expressed on cancer cells can provide protection from antitumor antibodies and may potentially modulate the induction of an immune response to tumor-associated antigens. In the current study, we investigated the consequences of complement inhibitor down-regulation on the effector and inductive phases of an immune response. Stable small interfering RNA-mediated down-regulation of the complement inhibitor Crry on MB49 murine bladder cancer cells increased their susceptibility to monoclonal antibody and complement in vitro. In a syngeneic model of metastatic cancer, the down-regulation of Crry on i.v.-injected MB49 cells was associated with a significant decrease in tumor burden and an increase in the survival of challenged mice. However, monoclonal antibody therapy had no additional benefit. There was an antitumor IgG response, but the response was not effected by Crry down-regulation on inoculated tumor cells. Down-regulation of Crry on MB49 cells resulted in an enhanced antitumor T-cell response in challenged mice (measured by lymphocyte IFN-gamma secretion), and CD8+ T cell depletion of mice prior to injection of MB49 cells completely abrogated the effect of Crry down-regulation on tumor burden and survival. Deficiency of C3 also abrogated the effect of Crry down-regulation on the survival of MB49-challenged mice, indicating a complement-dependent mechanism. These data indicate that complement inhibitors expressed on a tumor cell can suppress a T cell response and that enhancing complement activation on a tumor cell surface can promote protective T cell immunity.