ITOC2 – 015. Therapy of hepatocellular carcinoma (HCC) with immunostimulatory RNA activating RIG-I

Abstract

Background Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, leads to a median survival of less than one year, necessitating the search for new therapies. The cytosolic helicase RIG-I senses viral 5′-triphosphate-RNA (ppp-RNA) and induces type I interferon (IFN)-driven immune responses that combat both viral infections as well as tumours. RIG-I may thus serve as a new target for immunotherapy of HCC. Methods RIG-I expression in HCC was analysed by immunohistochemistry (IHC) and WB. RIG-I functional activity was assessed by transfection of HCC cells with ppp-RNA. Therapeutic efficacy was evaluated in vitro and in vivo in an orthotopic HCC mouse model. Seven days after tumour induction ppp-RNA was injected intravenous (i.v.) and survival was monitored. Tumour tissue was analysed via IHC and qRT-PCR. Results Treatment of human and murine HCC cells with ppp-RNA induced phosphorylation of IRF-3, production of IFN-b and CXCL10, indicative of intact RIG-I signalling. In addition, RIG-I activation led to profound tumour cell death. Treatment of mice with orthotopic HCC with ppp-RNA reduced tumour size and significantly prolonged survival. CD8+ T cells as well as NK cells mediated tumour rejection. Conclusion Our data demonstrate that RIG-I is functional in HCC. RIG-I activation leads to systemic and intratumoural type I IFN production accompanied by massive tumour cell death in vitro and in vivo . RIG-I is thus a promising novel target for HCC therapy deserving further evaluation.