Abstract
Human papillomavirus (HPV) 16 E7 (E7) protein expression in skin promotes epithelial hyperproliferation and transformation to malignancy. Grafts of murine skin expressing E7 protein as a transgene in keratinocytes are not rejected from immunocompetent recipients, whereas grafts expressing ovalbumin (OVA), with or without coexpression of E7 protein, are promptly rejected, demonstrating that E7-associated non-antigen-specific local immunosuppression is not a major determinant of lack of rejection of E7 transgenic skin. To determine whether failure of rejection of E7 skin grafts is due to failure to attract E7-specific effector T cells, E7- and OVA-specific effector CD8+ T cells, activated in vitro, were transferred to animals bearing E7 transgenic skin grafts. Three days after T cell transfer, E7-specific T cells were present in significantly greater numbers than OVA-specific T cells in the grafted skin on animals bearing recently placed or healed E7 grafts, without graft rejection, and also in the ear skin of E7 transgenic animals, without obvious pathology. E7 and OVA-specific T cells were present in lesser numbers in healed E7 grafts than in recently placed grafts and in lesser numbers in recently placed E7 transgenic epidermal grafts without E7-associated hyperproliferation, derived from E7 transgenic mice with a mutated retinoblastoma gene. These data demonstrate that effector T cells are to some extent attracted to E7 transgenic skin specifically by E7 expression, but in large measure non-specifically by the epithelial proliferation associated with E7 expression, and by the local inflammation produced by grafting. Failure of E7 graft rejection was observed despite trafficking of E7-specific effector T cells to E7-expressing epithelium, a finding of consequence for immunotherapy of HPV 16 E7-associated human cancers.
Highlights
Infection with some human papillomavirus (HPV) genotypes promotes development of cervical intraepithelial neoplasia and cervical cancer
We examined the fate of K14E7 skin grafts coexpressing OVA as a transgene from the K5 promoter, an antigen previously shown to induce skin graft rejection when expressed as a single transgene [15]
Grafts from K5mOVA and K14E7 × K5mOVA animals were each rejected by day 18 post grafting (Figure 1), with no evidence of delayed rejection due to the coexpression of E7. This finding suggests that failure of rejection of an K14E7 graft by an immunocompetent recipient reflects antigen-specific failure of effector T cell response necessary for graft rejection
Summary
Infection with some human papillomavirus (HPV) genotypes promotes development of cervical intraepithelial neoplasia and cervical cancer. About 5% of all human cancers are caused by infection with high risk HPV genotypes, HPV16, and HPV infection initiates more than 99% of cervical cancers, with over 260,000 related deaths [1]. Most high-risk HPV infections will be cleared within 5 years, infection is persistent in 1 to 2% of infected subjects and can progress to precancerous lesions and to cervical cancer if untreated [3, 4]. Increased regulatory T cells in lesions correlate with virus persistence and cancer progression, while regressing lesions show a dominance of CD8+ T cell infiltrates [5,6,7].
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