Recombinant human papillomavirus type 16 E7 protein as a model antigen to study the vaccine potential in control and E7 transgenic mice.
The early genes E6 and E7 of human papillomavirus type 16 (HPV16) are consistently and exclusively expressed in HPV16-induced cancer lesions and play major roles in the development and maintenance of the malignant phenotype. Because this protein is a good example of a tumor-associated antigen, we have used E7 as a model antigen to test the potential of an experimental vaccine as an immunotherapeutic approach. In this study, we used a murine E7-expressing tumor model (TC1 cells) to assess effects of an E7-based vaccine on tumor growth. We show that vaccination with the E7 protein, formulated in the SmithKline Beecham Biologicals proprietary adjuvants (SBAS 1 and SBAS 2), leads to the rejection of pre-established tumors. Tumor rejection was associated with the induction of a strong systemic T helper 1 response, including CTLs, and the presence of an inflammatory infiltrate within the regressing tumor. Because most identified tumor-associated antigens are self antigens rather viral antigens, we used E7 transgenic mice to evaluate the E7-based vaccine in conditions where E7 is a self antigen. Transgenic mice, which constitutively and specifically express the E7 HPV16 gene in the thyroid epithelium, rapidly develop thyroid goiters and, after several months, thyroid carcinomas. We show that E7-specific antibodies and CD4 T helper responses can be obtained by vaccinating E7 transgenic mice, although a CTL response was not detected. Despite the absence of measurable CTL responses, vaccination still reduced the growth of pre-established TC1 tumors, although less efficiently than in nontransgenic animals, but was unable to suppress or delay the development of the spontaneous thyroid pathology.
Gérard
C M
CM
GlaxoSmithKline Biologicals, Research and Development, Rixensart, Belgium. catherine.gerard@sbbio.be
Baudson
N
N
Kraemer
K
K
Ledent
C
C
Pardoll
D
D
Bruck
C
C
D000818:Animals; D019496:Cancer Vaccines; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis*; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D010957:Plasmids / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes
D019496:Cancer Vaccines; D007074:Immunoglobulin G; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D011994:Recombinant Proteins; C059731:oncogene protein E7, Human papillomavirus type 16