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.
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 E749-57 (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 E749-57-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 E749-57. In addition, effective immune memory after VLP immunization was maintained for at least 16 weeks, preventing significant tumor growth after subsequent TC-1 challenge.


CONCLUSIONS
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.
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, People's Republic of China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, People's Republic of China; Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease, Kunming, People's Republic of China.
Xiaojie
X
Chu
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, People's Republic of China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, People's Republic of China; Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease, Kunming, People's Republic of China.
Yang
Y
Li
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, People's Republic of China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, People's Republic of China; Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease, Kunming, People's Republic of China.
Qiong
Q
Long
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, People's Republic of China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, People's Republic of China; Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease, Kunming, People's Republic of China.
Ye
Y
Xia
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, People's Republic of China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, People's Republic of China; Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease, Kunming, People's Republic of China.
Yufeng
Y
Yao
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, People's Republic of China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, People's Republic of China; Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease, Kunming, People's Republic of China.
Wenjia
W
Sun
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, People's Republic of China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, People's Republic of China; Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease, Kunming, People's Republic of China.
Weiwei
W
Huang
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, People's Republic of China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, People's Republic of China; Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease, Kunming, People's Republic of China.
Xu
X
Yang
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, People's Republic of China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, People's Republic of China; Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease, Kunming, People's Republic of China.
Cunbao
C
Liu
Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, People's Republic of China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming, People's Republic of China; Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease, Kunming, People's Republic of China.
Yanbing
Y
Ma
D000818:Animals; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines / Q000276:immunology / Q000493:pharmacokinetics*; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology*; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D008810:Mice, Inbred C57BL; D053918:Papillomavirus Vaccines / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014611:Vaccination; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes; D006512:Hepatitis B Core Antigens; D053918:Papillomavirus Vaccines
cellular immune responses; human papillomavirus; therapeutic vaccine; tumor; virus-like particles