In vivo depletion of DC impairs the anti-tumor effect of agonistic anti-CD137 mAb
Murillo O., Dubrot J., Palazón A., Arina A., Azpilikueta A., Alfaro C., Solano S., Ochoa M.C., Berasáin C., Gabari I., Pérez-Gracia J.L., Berraondo P., Hervás-Stubbs S., Melero I.
Gene Therapy Unit, Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain
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.
CITATION Eur J Immunol. 2009 Sep;39(9):2424-36