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

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.

A Hepatitis B Virus-Derived Peptide Can Inhibit Infection of Human Lung Cells with SARS-CoV-2 in a Type-1 Interferon-Dependent Manner

“…Recently, we have reported that Poly6 can lead to TNF/iNOS-producing (Tip) DC, mediating an anticancer effect via enhanced IFN-I in vaccinated mice [ 15 ]. Therefore, we further investigated the antiviral mechanism of Poly6, focusing on IFN-I as a potential antiviral signaling molecule.…”

“…Based on the hypothesis that a 6-mer peptide (Poly6 of the overlapping polymerase corresponding to preS1 deletion could be involved in HBV replication due to the related antiviral responses ( Figure 1 A we reported that a Poly6 peptide derived from the hepatitis B virus (HBV polymerase could elicit an antiviral effect against human immunodeficiency virus-1 (HIV-1) by suppressing viral integration in infected cells, mainly via inhibition of acetylation of HIV-1 integrase [ 14 ]. Moreover, we recently reported that Poly6 could elicit a strong anticancer immune response via TNF/iNOS-producing dendritic cells in an IFN-I-dependent manner in a tumor-bearing mouse model [ 15 ]. Therefore, in this study, we sought to evaluate the potential of Poly6 as a novel SARS-CoV-2 inhibitor in the human bronchial epithelial cell line, Calu-3, mainly focusing on enhanced IFN-I production.…”

A hepatitis B virus-derived peptide combined with HBsAg exerts an anti-HBV effect in an HBV transgenic mouse model as a therapeutic vaccine

“…Therefore, to further investigate DC migration capacity by Poly6, we performed a migration assay using mouse footpad injection. BMDCs treated with PBS, Poly6, or LPS were labeled with As we had verified that Poly6 induced strong immune responses through type I IFN signaling in our previous studies (21,28), in this study, we examined whether vaccination with Poly6 in combination with HBsAg facilitated DC maturation in a type I IFN-dependent manner by comparing DC activities between C57BL/6 and IFNAR KO mice. Six-to eight-week-old C57BL/6 or IFNAR KO mice were vaccinated in a prime-boost regimen (Figure 1D), and mouse splenocytes were assessed for DC maturation by flow cytometry.…”

“…As professional APCs, DCs play a crucial role in facilitating antigen-specific T-cell responses in chronic HBV infection (23,24). As our previous study revealed that Poly6 exerted a strong anticancer effect in tumor-implanted mice via iNOS-producing DCs (21), we examined whether Poly6 itself could promote the maturation and migration capacity of DCs in BMDCs (Figure 1; Supplementary Figure 2). The murine DC population was selected in high purity (Figure 1A), and MHCII, CD86, CD83, and CCR7 were evaluated by flow cytometry 24 h poststimulation.…”

“…Type 1 interferon (IFN-I), with a strong anti-HBV activity, can also elicit DC maturation and augment cross presentation of antigens in DCs, resulting in NK cell-mediated and CTLmediated antitumor or antiviral effects in mice (20). Recently, we reported that an HBV-derived 6-mer peptide, Poly6, exerts a strong anticancer effect in mice implanted with MC38 cells, a murine colon adenocarcinoma line, through the production of inducible nitric oxide synthase (iNOS)-producing DCs (Tip-DCs) in a type 1 interferon (IFN-I)-dependent manner (21), suggesting that Poly6, as an IFN-I inducer, may be a potential vaccine adjuvant for use in antivirus therapy, such as HBV therapeutic vaccines.…”