Murillo Oihana, Dubrot Juan, Palazón Asís, Arina Ainhoa, Azpilikueta Arantza, Alfaro Carlos, Solano Sarai, Ochoa María C, Berasain Carmen, Gabari Izaskun, Pérez-Gracia José L, Berraondo Pedro, Hervás-Stubbs Sandra, Melero Ignacio
Gene Therapy Unit, Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain.
Eur J Immunol. 2009 Sep;39(9):2424-36. doi: 10.1002/eji.200838958.
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 CD8beta(+) 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.
抗CD137单克隆抗体能够在多种同基因小鼠肿瘤模型中诱导肿瘤排斥反应，并且正在进行癌症临床试验。其抗肿瘤作用涉及对肿瘤特异性CD8(+) T细胞的共刺激。抗CD137单克隆抗体治疗的疗效是否需要抗原交叉呈递树突状细胞（DC）从未被研究过。在此我们表明，抗CD137单克隆抗体的给药通过一种严格依赖CD8β(+) T细胞的机制根除EG7-OVA肿瘤，该机制与CTL活性增加相关。体外分析以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CD11c(+)细胞，很可能是DC，是该肿瘤模型中的主要参与者。通过OVA cDNA的存在揭示，少量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的诱导。使用CD11c白喉毒素受体-绿色荧光蛋白→C57BL/6骨髓嵌合小鼠，其允许用白喉毒素持续清除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以及抗CD137单克隆抗体诱导的抗肿瘤疗效。
