A Hepatitis B Virus-Derived Peptide Exerts an Anticancer Effect via TNF/iNOS-producing Dendritic Cells in Tumor-Bearing Mouse Model

SIMPLE SUMMARY: Recently, it has been reported that a tumor necrosis factor (TNF)/inducible nitric oxide synthase (iNOS)-producing dendritic cell (Tip-DC) may play a pivotal role in the anticancer immune response by activating CD8+ T cells in tumor microenvironments. The development of a new immunotherapeutic agent that can enhance the oncolytic effect of Tip-DC has gained increasing attention in the cancer research field. In this study, we introduce a hepatitis B virus-derived peptide, Poly6, which elicited a strong anticancer immune response via enhanced Tip-DC activity. Our findings suggest that Poly6 could be a novel potential adjuvant/co-treatment partner in anticancer immunotherapy approaches. ABSTRACT: Recently, we reported a 6-mer hepatitis B virus (HBV)-derived peptide, Poly6, that exerts antiviral effects against human immunodeficiency virus type 1 (HIV-1). Here, we explored the immunotherapeutic potential of Poly6 via its administration into dendritic cells (DCs) in a mouse model. Our data revealed that Poly6 treatment led to enhanced production of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS)-producing DCs (Tip-DCs) in a type 1 interferon (IFN-I)-dependent manner via the induction of mitochondrial stress. Poly6 treatment in mice implanted with MC38 cells, a murine colon adenocarcinoma line, led to attenuated tumor formation, primarily due to direct cell death induced by Tip-DC mediated nitric oxide (NO) production and indirect killing by Tip-DC mediated cluster of differentiation 8 (CD8) cytotoxic T lymphocyte (CTL) activation via CD40 activation. Moreover, Poly6 treatment demonstrated an enhanced anticancer effect with one of the checkpoint inhibitors, the anti PD-L1 antibody. In conclusion, our data reveal that Poly6 treatment elicits an antitumor immune response in mice, possibly through NO-mediated oncolytic activity via Tip-DC activation and Tip-DC mediated CTL activation. This suggests that Poly6 represents a potential adjuvant for cancer immunotherapy by enhancing the anticancer effects of immune checkpoint inhibitors.