In vivo depletion of DC impairs the anti-tumor effect of agonistic anti-CD137 mAb
In vivo depletion of DC impairs the anti-tumor effect of agonistic anti-CD137 mAb
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DOI：
10.1002/eji.200838958
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发表时间：
2009-09-01
影响因子：
5.4
通讯作者：
Melero, Ignacio
中科院分区：
文献类型：
--
作者：
Murillo, Oihana;Dubrot, Juan;Melero, Ignacio
抗CD 137 mAb能够在几种同系小鼠肿瘤模型中诱导肿瘤排斥反应，目前正在进行癌症临床试验。抗肿瘤作用涉及肿瘤特异性CD 8（+）T细胞的共刺激。尚未研究抗CD 137 mAb治疗的疗效是否需要抗原交叉呈递DC。在此，我们发现抗CD 137单克隆抗体通过严格的CD 8 β（+）T细胞依赖性机制根除EG 7-OVA肿瘤，该机制与CTL活性增加相关。体外分析确定负责肿瘤抗原交叉呈递的引流淋巴结细胞类型的身份，结果显示CD 11 c（+）细胞（最有可能是DC）是该肿瘤模型中的主要参与者。卵清蛋白cDNA的存在表明，极少量的肿瘤细胞到达肿瘤引流淋巴结。肿瘤细胞自身的直接抗原呈递也参与抗OVA CTL诱导。使用CD 11 c白喉毒素受体-绿色荧光蛋白-> C57 BL/6 BM嵌合小鼠，其允许用白喉毒素持续消融DC，我们证实了DC参与针对OVA（257-264）表位的CTL诱导中的肿瘤抗原交叉呈递和抗CD 137 mAb诱导的抗肿瘤功效。
Anti-CD137 mAb are capable of inducing tumor rejection in several syngeneic murine tumor models and are undergoing clinical trials for cancer. The anti-tumor effect involves co-stimulation of tumor-specific CD8(+) T cells. Whether antigen cross-presenting DC are required for the efficacy of anti-CD137 mAb treatment has never been examined. Here we show that the administration of anti-CD137 mAb eradicates EG7-OVA tumors by a strictly CD8 beta(+) T-cell-dependent mechanism that correlates with increased CTL activity Ex vivo analyses to determine the identity of the draining lymph node cell type responsible for tumor antigen cross-presentation revealed that CD11c(+) cells, most likely DC, are the main players in this tumor model. A minute number of tumor cells, revealed by the presence of OVA cDNA, reach tumor-draining lymph nodes. Direct antigen presentation by tumor cells themselves also participates in anti-OVA CTL induction. Using CD11c diphtheria toxin receptor-green fluorescent protein -> C57BL/6 BM chimeric mice, which allow for sustained ablation of DC with diphtheria toxin, we confirmed the involvement of DC in tumor antigen cross-presentation in CTL induction against OVA(257-264) epitope and in the antitumor efficacy induced by anti-CD137 mAb.