Chimeric HBcAg virus-like particles presenting a HPV 16 E7 epitope significantly suppressed tumor progression through preventive or therapeutic immunization in a TC-1-grafted mouse model

Abstract

Background

Therapeutic human papillomavirus (HPV) vaccines are currently being developed. However, no therapeutic efficacy has been achieved in clinical trials for the treatment of cervical intraepithelial neoplasia or cancer. One of the important issues in increasing vaccine efficacy is determining the best way to enhance tumor antigen-specific cellular immune responses. This study aimed to explore the virus-like particles (VLPs) of hepatitis B core antigen (HBcAg) as potential therapeutic vaccine carriers and to assess its immunological characteristics.

Methods

Chimeric VLPs presenting a HPV 16 cytotoxic T lymphocytes epitope E7_49–57 (amino acid 49–57 of the E7 protein) were prepared using recombinant genes. C57BL/6 mice were immunized with VLPs and grafted with tumor cells TC-1 which is an E7-expressing tumorigenic cell line. The dynamic tumor growth was monitored and anti-tumor immune responses were investigated.

Results

Using a preventive strategy, immunization with VLPs resulted in nearly complete suppression of tumor growth. In treatment studies, VLP immunization significantly suppressed the tumor progression in mice carrying 2–3 mm tumors and in those bearing even larger tumors with diameters up to 8–9 mm. The VLP structure was shown to be important to induce vigorous antitumor immunity and effects. In immunized mice, enhanced E7_49–57-specific cellular immune responses were evidenced by increased interferon (IFN)-γ expression and decreased interleukin (IL)-4 expression in splenic lymphocytes, as well as an elevated number of effector cells expressing IFN-γ in response to the in vitro stimulation of the specific peptide E7_49–57. In addition, effective immune memory after VLP immunization was maintained for at least 16 weeks, preventing significant tumor growth after subsequent TC-1 challenge.

Conclusion

While VLPs were highly immunogenic in stimulating humoral immunity, our results strongly indicated that VLPs, such as HBcAg particles, might also be potent therapeutic vaccine carriers to elicit robust cellular immune responses, even in the immunosuppressive microenvironment of a tumor.

Keywords:

• cellular immune responses
• human papillomavirus
• tumor
• therapeutic vaccine
• virus-like particles

Acknowledgments

This work was supported by Fundamental Research Funds for the Central Universities of China (2012N08) and Applied Basic Research Projects of Yunnan Province, People’s Republic of China, from Yunnan Provincial Science and Technology Department (2010ZC232 and 2013FZ137), Fundamental Research Funds for Institute of Pathogen Biology of Peking Union Medical College (2014IPB107), the Peking Union Medical College (PUMC) Youth Fund, the Fundamental Research Funds for the Central Universities of China (3332015197 and 3332015147). The authors thank Mr Jingxian Zhou for excellent assistance in electron microscopy.

Disclosure

The authors report no conflict of interest in this work.