Alarmin augments the antitumor immunity of lentiviral vaccine in ectopic, orthotopic and autochthonous hepatocellular carcinoma mice

Abstract

It is a daunting therapeutic challenge to completely eradicate hepatocellular carcinoma (HCC) from patients. Alpha-fetoprotein (AFP) -based vaccines appear promising, however the efficacy needs to be improved. Methods: Here, we explore if fusing high-mobility group nucleosome binding protein 1 (HMGN1), a potent immunoadjuvant, to AFP (lenti-HA) can augment the antitumor immunity of AFP-expressing lentiviral vector (lenti-AFP), a vehicle extensively employed for genetic immunization with high transduction efficacy and good safety profiles. The antitumor immunity of Lenti-HA was systemically assessed in ectopic, orthotopic and autochthonous HCC models. Results: Lenti-HA elicited strong anti-HCC effects in mice and amplified the antitumor immunity of lenti-AFP by reducing effective dose 6-fold. Importantly, lenti-HA induced a robust antitumor immune response with prolonged survival rate and improved the immune and tumor microenvironment in mice with carcinogen-induced autochthonous HCC. Lenti-HA localized primarily to lymphoid organs with no preference for specific immune cell types. Activated dendritic cells (DCs), particularly CD103+CD11b- DCs, were also actively recruited to lymph nodes in lenti-HA-treated HCC mice. Moreover, lenti-HA-transduced human DCs elicited stronger immune response than lenti-AFP against HCC cells in vitro. Conclusion: Our study demonstrates that HMGN1 augments the antitumor immunity of AFP-expressing lentiviral vaccines in HCC mice and human cells in vitro and thus provides a new therapeutic strategy for HCC.