Skin delivery of short hairpin RNA of indoleamine 2,3 dioxygenase induces antitumor immunity against orthotopic and metastatic liver cancer

Abstract

Liver cancer is one of the most malignant cancers in the world and has a high rate of metastasis. Therefore, development of a novel therapy for liver cancer is a critical issue. Indoleamine 2,3-dioxygenase (IDO) is known as a negative immune regulator in dendritic cells. Our previous study demonstrated that skin delivery of IDO short hairpin RNA (shRNA) induced antitumor immunity in subcutaneous bladder and colon tumor models. Because the immunological environment is quite different between skin and liver, it is essential to evaluate whether skin delivery of IDO shRNA is an effective treatment in metastatic and orthotopic animal tumor models. In the present study, IDO shRNA inhibited tumor growth in subcutaneous, metastatic and orthotopic liver tumor models. The cytotoxicity of splenocytes was significantly elevated in mice treated with IDO shRNA in the orthotopic and metastatic tumor models. Interleukin (IL)-12 and interferon (IFN)-gamma mRNA expression were upregulated while IL-10 was downregulated in the inguinal lymph nodes, which were collected from IDO shRNA-treated mice. Similar results were observed in the spleens of mice inoculated with IDO shRNA by gene gun. The results indicate that skin administration of IDO shRNA is an effective therapy in orthotopic and metastatic liver cancer animal models. Indoleamine 2,3-dioxygenase shRNA might be a potential new treatment for liver cancer in the future.