Novel oligomannose liposome-DNA complex DNA vaccination efficiently evokes anti-HPV E6 and E7 CTL responses.
The aim of this study was to establish an efficient human papilloma virus (HPV) type 16-targeting cancer immunotherapy. Persistent high-risk HPV infection causes cervical intra-epithelial neoplasia (CIN) and subsequent cervical carcinoma. HPV type16 (HPV16) is one of the common carcinogenic types and is found in about 50% of invasive cervical carcinomas. HPV16-derived viral proteins E6 and E7 are expressed in cancerous cells through the progression of the disease and have a role in carcinogenesis but are not expressed in normal cells. Thus, these proteins are regarded as ideal antigens for cervical carcinoma immunotherapy. In this study, we generated a novel HPV 16 E6 and E7 gene plasmid containing oligomannose liposomes (OML-HPV). We compared the cytotoxic T lymphocyte (CTL) induction efficiency of OML-HPV and that of standard liposome-HPV16 E6 and E7 DNA complex. HPV16 E6-specific CTLs could be generated from HPV 16-positive cervical carcinoma patient's peripheral blood mononuclear cells (PBMCs) by stimulating OML-HPV, but could not by stimulating standard liposome-HPV 16 E6, E7 DNA complex. Furthermore, we screened HLA-A24-restricted HPV16 E6- and E7-derived peptides, and found that one E6-derived peptide (E6 66-74) showed the highest immunogenicity with ELISPOT assay from 100% of HPV16-positive patients (4 out of 4). On the other hand, other E6- or E7-derived peptides, including E6 49-57, E6 82-90, E6 87-95, E6 98-106 and E7 83-93, showed less frequent reactivity. These results indicate that OML-HPV is a more effective approach than DNA vaccination using standard liposomes, and that a novel HLA-A24-restricted peptide, E6 66-74, might be a suitable target of cervical cancer immunotherapy.
Department of Pathology, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-Ku, Sapporo 060-8556, Japan.
Masahito
M
Mizuuchi
Yoshihiko
Y
Hirohashi
Toshihiko
T
Torigoe
Takafumi
T
Kuroda
Kazuyo
K
Yasuda
Yoshitaka
Y
Shimizu
Tsuyoshi
T
Saito
Noriyuki
N
Sato
D000328:Adult; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D005838:Genotype; D059871:HLA-A24 Antigen / Q000276:immunology; D006801:Humans; D008081:Liposomes; D008213:Lymphocyte Activation / Q000276:immunology; D008358:Mannose / Q000008:administration & dosage; D008875:Middle Aged; D009844:Oligosaccharides / Q000008:administration & dosage; D009856:Oncogene Proteins, Viral / Q000276:immunology; D027383:Papillomaviridae / Q000276:immunology*; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D030361:Papillomavirus Infections / Q000276:immunology* / Q000821:virology; D010957:Plasmids; D012097:Repressor Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000821:virology; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage*; D002578:Uterine Cervical Dysplasia / Q000276:immunology* / Q000821:virology
D004279:DNA, Viral; C068651:E6 protein, Human papillomavirus type 16; D059871:HLA-A24 Antigen; D008081:Liposomes; D009844:Oligosaccharides; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16; D008358:Mannose