專題討論2：癌症的免疫治療
Cancer Immunotherapy

S2-5
A Novel Cancer Therapy by Skin Delivery of Indoleamine 2,3-dioxygenase siRNA
Meng-Chi Yen1, Chi-Chen Lin2, Yi-Ling Chen3, and Ming-Derg Lai1
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University1
Institute of Medical Technology, College of Life Sciences, National Chung Hsing University, No. 250, Kuo Kuang Road, Taichung.2
Department of Childhood Education and Nursery, Chia Nan University of Pharmacy and Science, No. 60, Erh-Jen Road, Sec.1, Jen-Te, Tainan 3

Dendritic cells are usually prepared ex vivo and pulsed with tumor antigens to generate anti-tumor immunity. In this article, we have demonstrated that physical delivery of siRNA targeting indoleamine 2,3-dioxygenase (IDO) in vivo can produce an effective anti-tumor immune response without loading specific tumor antigens. ndoleamine 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 DCs 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 downregulated in CD11c+ 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 immunological rejection because the effect was abolished by depletion of CD8+ T cells. Adoptive transfer of CD11c+ DCs 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 therapeutic efficacy of Her2/Neu DNA vaccine. Downregulation of IDO2, an IDO homologue, with siRNA also generated antitumor immunity in vivo. Conclusion: This simple non-viral method reduce lengthy working in preparation of dendritic cells ex vivo, and may be useful in treating various types of tumors because the immune response is not limited on a particular tumor antigen. Furthermore, the immune response can be directed to a tumor-associated antigen as demonstrated by co-delivery of neu DNA vaccine and IDO siRNA.
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