Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy
Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy
复制标题
DOI：
10.1084/jem.20031457
复制
发表时间：
2004-02-16
影响因子：
15.3
通讯作者：
Smyth, MJ
中科院分区：
文献类型：
--
作者：
Takeda, K;Yamaguchi, N;Smyth, MJ
肿瘤坏死因子相关的凋亡诱导配体(TRAIL)优先诱导肿瘤细胞凋亡，在肿瘤监测中发挥重要作用，其受体是抗体介导肿瘤治疗的重要靶点。在此，我们报道了一种针对小鼠TRAIL受体的单抗DR5，通过募集表达Fc受体的天然免疫细胞，在体内对TRAIL敏感的肿瘤细胞显示出强大的抗肿瘤作用，而没有明显的全身毒性。给予激动型抗DR5单抗也能显著抑制实验性和自发性肿瘤转移。值得注意的是，天然免疫细胞通过抗DR5单抗介导的肿瘤排斥反应有效地激发了肿瘤特异性T细胞免疫，也可以根除TRAIL耐药变体。这些结果表明，以DFG为靶点的抗体治疗是一种有效的策略，不仅可以消除TRAIL敏感的肿瘤细胞，而且还可以诱导肿瘤特异性T细胞记忆，从而提供长期的肿瘤复发保护。
Because tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells and plays a critical role in tumor surveillance, its receptor is an attractive target for antibody-mediated tumor therapy. Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity. Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases. Notably, the anti-DR5 mAb-mediated tumor rejection by innate immune cells efficiently evoked tumor-specific T cell immunity that could also eradicate TRAIL-resistant variants. These results suggested that the antibody-based therapy targeting DFG is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.