Anti-4-1BB monoclonal antibody enhances rejection of large tumor burden by promoting survival but not clonal expansion of tumor-specific CD8+ T cells.
Anti-4-1BB monoclonal antibody enhances rejection of large tumor burden by promoting survival but not clonal expansion of tumor-specific CD8+ T cells.
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发表时间：
2002-06
期刊：
影响因子：
11.2
通讯作者：
K. May;Lieping Chen;P. Zheng;Yang Liu
中科院分区：
文献类型：
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作者：
K. May;Lieping Chen;P. Zheng;Yang Liu
抗4-1BB单抗可通过依赖于CD4/CD8的机制诱导抗肿瘤免疫，但其在肿瘤排斥反应中对肿瘤特异性CD8+T细胞的直接作用尚不清楚。在这里，我们使用针对未突变的肿瘤排斥抗原P1a的转基因CD8+T细胞来分析该单抗是否能够在没有CD4+T辅助细胞的情况下促进CD8+T细胞对抗大肿瘤的功能。用表达P1a的浆细胞瘤J558攻击RAG-2(-/-)小鼠。一旦肿瘤直径达到0.85-1.75 cm，小鼠接受P1a特异性CD8+CTL(P1CTL)联合抗4-1BB单抗或对照免疫球蛋白的治疗。所有小鼠的肿瘤都有部分消退，但抗4-1BB单抗治疗的小鼠表现出明显的肿瘤排斥反应，延缓了肿瘤的进展，延长了生存时间。相应地，我们观察到抗4-1BB单抗处理的小鼠的P1CTL数量显著增加。令人惊讶的是，抗4-1BB单抗并没有加速肿瘤特异性CD8+T细胞的分裂，肿瘤特异性T细胞数量的增加是由于激活诱导的细胞死亡减少。这些结果表明，抗4-1BB单抗可以在没有CD4+T细胞帮助的情况下，通过促进P1CTL存活而不增加初始克隆扩增来促进CD8+T细胞介导的对大肿瘤的保护。
Anti-4-1BB monoclonal antibody (mAb) has been shown to induce antitumor immunity by a CD4/CD8-dependent mechanism, but its direct effect on tumor-specific CD8+ T cells in tumor rejection is unclear. Here we used transgenic CD8+ T cells against the unmutated tumor rejection antigen P1A to analyze whether this mAb can promote CD8+ T-cell function against large tumors in the absence of CD4+ T-helper cells. RAG-2(-/-) mice were challenged with P1A-expressing plasmacytoma J558. Once tumor size reached a diameter of 0.85-1.75 cm, mice were treated with P1A-specific CD8+ CTL (P1CTL) in conjunction with anti-4-1BB mAb or control IgG. All of the mice showed a partial regression of tumor, but mice treated with anti-4-1BB mAb exhibited markedly enhanced tumor rejection, delayed tumor progression, and prolonged survival. Correspondingly, we observed a substantial increase in the number of P1CTL in anti-4-1BB mAb-treated mice. Surprisingly, anti-4-1BB mAb did not accelerate division of the tumor-specific CD8+ T cells, and the increase in tumor-specific T-cell number was due to reduced activation-induced cell death. These results indicate that anti-4-1BB mAb can promote CD8+ T cell-mediated protection against large tumors in the absence of CD4+ T-cell help by promoting P1CTL survival without increasing initial clonal expansion.