A novel cancer therapy by skin delivery of indoleamine 2,3-dioxygenase siRNA.
OBJECTIVE
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.


METHODS
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.


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 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.


CONCLUSIONS
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.
Yen
Meng-Chi
MC
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.
Lin
Chi-Chen
CC
Chen
Yi-Ling
YL
Huang
Shih-Shien
SS
Yang
Huei-Jiun
HJ
Chang
Chih-Peng
CP
Lei
Huan-Yao
HY
Lai
Ming-Derg
MD
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D039521:CD11c Antigen / Q000096:biosynthesis; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000378:metabolism; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D034741:RNA, Small Interfering / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000378:metabolism*
D000970:Antineoplastic Agents; D039521:CD11c Antigen; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D034741:RNA, Small Interfering