A Novel Cancer Therapy by Skin Delivery of Indoleamine 2,3-Dioxygenase siRNA

Abstract

Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan, is a negative immune regulatory molecule of dendritic cells. IDO-expressing dendritic cells suppress T cell responses and may be immunosuppressive in vivo. We hypothesized that silencing the IDO expression in skin dendritic cells in vivo could elicit antitumor activity in tumor-draining lymph nodes. The efficiency of 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. 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 T cells and neutrophils increased at tumor sites, which are correlated with therapeutic efficacy. The T cells may be mainly responsible for the immunologic rejection because the effect was abolished by depletion of CD8-positive T cells. Adoptive transfer of CD11c-positive dendritic cells from vaccinated mice delayed tumor progression. The cancer therapeutic effect was reproducibly observed with 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 efficacy of Her2/Neu DNA vaccine. Down-regulation of IDO2, an IDO homologue, with siRNA also generated antitumor immunity in vivo. Antitumor immunity can be effectively elicited by physical delivery of siRNAs targeting immunoregulatory genes in skin dendritic cells in vivo, as shown by IDO and IDO2 in this report.