Preventive Inhibition of Liver Tumorigenesis by Systemic Activation of Innate Immune Functions

Abstract

Summary: Liver cancer has become the second most deadly malignant disease, with no efficient targeted or immune therapeutic agents available yet. While dissecting the roles of cytoplasmic signaling molecules in hepatocarcinogenesis using an inducible mouse gene targeting system, Mx1-cre, we identified a potent liver tumor-inhibitory effect of synthetic double-stranded RNA (dsRNA), polyinosinic-polycytidylic acid (pIC), an inducer of the Mx1-cre system. Injection of pIC at the pre-cancer stage robustly suppressed liver tumorigenesis either induced by chemical carcinogens or by Pten loss and associated hepatosteatosis. The immunostimulatory dsRNA inhibited liver cancer initiation, apparently by boosting multiple anti-tumor activities of innate immunity, including induction of immunoregulatory cytokines, activation of NK cells and dendritic cells, and reprogramming of macrophage polarization. This study paves the way for the development of preventive and early interfering strategies for liver cancer to reduce the rapidly increasing incidences of liver cancer in an ever-growing population with chronic liver disorders. : Lee et al. report an inhibitory effect of pIC on liver cancer initiation through activating NK cells, reprogramming M1 and M2 macrophages, promoting injured hepatocyte death, and suppressing tumor cell genesis and expansion. Keywords: liver cancer, dsRNA, macrophage polarization, innate immune system, immunotherapy, preventive therapy, liver tumor-initiating cells