HPV16E7 tumor antigen modified by KDEL sequence induce specific cytotoxic T lymphocytes-dependent antitumor immunity.
BACKGROUND
Infection by high-risk HPV (human papillomavirus) is the primary cause of cervical cancer. Dendritic cell-based (DC-based) therapeutic vaccine represents a promising approach to the prevention and treatment of many cancers, including HPV-related cancers, but current strategies have met with only limited success in preclinical and clinical research. It is necessary to find a properly and effective antigen presenting system of DC-based vaccine.


OBJECTIVE
To design a new HPV16 therapeutic vaccine using an endoplasmic reticulum (ER) retrieval signal and study its ability to induce the specific CTL activity in vitro and in vivo.


METHODS
E7(p)-KDEL and its control peptide were synthesized on solid phase. A series of methods were used, including standard (51)Cr-labeled release assay, enzyme-linked immunospot (ELISPOT) assay and ELISA, to detect the CTL activity induced by different peptides. Prophylactic models and therapeutic models were examined to detect the in vivo effectiveness of E7(p)-KDEL-loaded DCs.


RESULTS
The specific CTL activity induced by E7(p)-KDEL-loaded DCs was much stronger than that induced by the other peptide-loaded DCs. Comparing with the control peptides, after incubation with the spleen cells of mice, the E7(p)-KDEL-loaded DCs could induce higher concentration of secreted IFN-gamma and had higher ELISPOT numbers. In animal models, E7(p)-KDEL-loaded DCs vaccines effectively protected mice against fatal TC-1 tumor challenge and cured tumor-bearing mice.


CONCLUSIONS
The ER retrieval signal-mediated antigen delivery system may have important clinical application for cancer therapy, even virus infectious disease and autoimmune disease.
Yin
Rui
R
Department of Dermatology, Southwest Hospital, Third Military Medical University, District Shapinba, Chongqing 400038, China. swyinrui@163.com
Zheng
Wenjie
W
Hao
Fei
F
Yang
Xi-Chuan
XC
Zhong
Bai-Yu
BY
Li
Qin-Jie
QJ
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D002461:Cell Line, Transformed; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D015195:Drug Design; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D007111:Immunity, Cellular; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control / Q000628:therapy* / Q000821:virology; D009842:Oligopeptides / Q000276:immunology*; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines / Q000276:immunology*; D021382:Protein Sorting Signals; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D013997:Time Factors
D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D009842:Oligopeptides; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D021382:Protein Sorting Signals; C059731:oncogene protein E7, Human papillomavirus type 16; C073762:lysyl-aspartyl-glutamyl-leucine; D007371:Interferon-gamma