Dissimilar immunogenicities of human papillomavirus E7 and adenovirus E1A proteins influence primary tumor development.
Although human papillomaviruses (HPV) and adenoviruses (Ad) both transform cells by expressing functionally related oncogenes (Ad-E1A/E1B; HPV-E7/E6), only HPV are oncogenic in humans. Prior studies have shown that HPV-transformed cells are resistant to NK cell lysis and E7- and E6-specific CTL are inefficiently generated in women with HPV-induced cervical cancer. Therefore, we postulated that the dissimilar oncogenicities of Ad and HPV may be caused by a protective NK and T cell response that is triggered by transformed cells expressing E1A, but not by E7. To test this hypothesis, mice that were either immunologically intact, lacked T cells, or lacked both NK and T cells were challenged with Ad serotype 5 (Ad5)-E1A- or HPV16-E7-transfected tumor cells. E7-expressing tumor cells were resistant to NK cell lysis in vitro and failed to elicit a measurable anti-tumor NK or T cell response in vivo. The concomitant expression of E6 did not change this phenotype. In contrast, E1A-expressing tumor cells were sensitive to NK lysis in vitro and triggered a protective NK and T cell immune response in vivo. These data suggest differences in the capacities of E1A or E7 oncoproteins to trigger protective anti-tumor immune responses may contribute to the dissimilar oncogenicities of Ad and HPV in humans.
Routes
J M
JM
Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado, 80206, USA. routesj@njc.org
Ryan
S
S
Li
H
H
Steinke
J
J
Cook
J L
JL
D017500:Adenovirus E1A Proteins / Q000276:immunology*; D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D003602:Cytotoxicity, Immunologic; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000821:virology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D009857:Oncogenes; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D012703:Serotyping; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16