Purpose: Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan, is a negative immune regulatorym olecule of dendritic cells. IDO-expressing dendritic cells suppress Tcell responses and maybe immunosuppressive in vivo.We hypothesized that silencing the IDO expression in skin dendritic cells in vivo could elicit antitumor activityi n tumor-draining lymph nodes.
Experimental Design: The efficiencyo f IDO-specific small interfering RNA (siRNA) was evaluated in vitro and in vivo. The therapeutic effect was evaluated in MBT-2 murine bladder tumor model and CT-26 colon tumor models.
Results: IDO expression was down-regulated in CD11c-positive lymphocytes after IDO siRNA treatment. In vivo skin administration of IDO siRNA inhibited tumor growth and prolonged survival in both tumor models. The number of infiltrated Tcells and neutrophils increased at tumor sites, which are correlated with therapeutic efficacy.TheTcells may be mainly responsible for the immunologic rejection because the effect was abolished byd epletion of CD8-positiveT cells.
Adoptive transfer of CD11c-positive dendritic cells from vaccinated mice delayed tumor progression. The cancer therapeutic effect was reproduciblyobservedwith another IDO siRNA targeting at different site, suggesting the effect was not due to off-target effect. In a neu-overexpressing MBT-2 tumor model, IDO siRNA enhanced the therapeutic efficacyo f Her2/Neu DNA vaccine. Down-regulation of IDO2, an IDO homologue, with siRNA also generated antitumor immunity
Conclusions: Antitumor immunityca n be effectively elicited by physical deliveryof siRNAs targeting immunoregulatoryg enes in skin dendritic cells in vivo, as shown byI DO and IDO2 in this report.