Abstract
Human Papillomavirus (HPV) 16 E7 protein promotes the transformation of HPV infected epithelium to malignancy. Here, we use a murine model in which the E7 protein of HPV16 is expressed as a transgene in epithelium to show that mast cells are recruited to the basal layer of E7-expressing epithelium, and that this recruitment is dependent on the epithelial hyperproliferation induced by E7 by inactivating Rb dependent cell cycle regulation. E7 induced epithelial hyperplasia is associated with increased epidermal secretion of CCL2 and CCL5 chemokines, which attract mast cells to the skin. Mast cells in E7 transgenic skin, in contrast to those in non-transgenic skin, exhibit degranulation. Notably, we found that resident mast cells in E7 transgenic skin cause local immune suppression as evidenced by tolerance of E7 transgenic skin grafts when mast cells are present compared to the rejection of mast cell-deficient E7 grafts in otherwise competent hosts. Thus, our findings suggest that mast cells, recruited towards CCL2 and CCL5 expressed by epithelium induced to proliferate by E7, may contribute to an immunosuppressive environment that enables the persistence of HPV E7 protein induced pre-cancerous lesions.
Highlights
Cervical and other anogenital cancers represent around 5% of all cancers, and are mostly due to infection of anogenital epithelium by one of more than 15 recognized ‘‘high risk’’ human papillomaviruses (HPV) [1]
We show that Mast cells (MCs) are recruited preferentially to the basal layer of HPV16 E7 expressing epithelium, that this recruitment is dependent on HPV16 E7 induced epithelial hyperproliferation, and that it is likely MCs are recruited by a CCL2/CCL5 dependent mechanism
Around 50% of sexually active women are believed to become infected by Human papillomavirus type 16, the major cause of cervical cancer, and 2% will remain infected and at lifetime risk of developing cancer
Summary
Cervical and other anogenital cancers represent around 5% of all cancers, and are mostly due to infection of anogenital epithelium by one of more than 15 recognized ‘‘high risk’’ human papillomaviruses (HPV) [1]. Most high risk HPV infections spontaneously regress, 1 to 2% of infected subjects develop persistent infection, which can progress to precancerous lesions, and to cervical cancer if untreated [2]. In HPV associated cancers, MCs occur in HPV induced premalignant CIN 2/3 lesions at twice the frequency observed in normal cervix [5]. Most CIN2/3 lesions, as well as cervical cancers, are known to be associated with infection of highrisk HPVs [6,7]. We used HPV16-K14.E7 transgenic mice, in which sustained expression of HPV16 E7 protein in keratinocytes mimics pre-cancerous lesions caused by HPV infection, to address three important questions. Does HPV16 E7 expression recruit MCs toward the epithelium? Do MCs recruited juxtaposed to the epithelium by HPV16 E7 expression mediate local immune suppression? Does HPV16 E7 expression recruit MCs toward the epithelium? Secondly, what mechanistic pathway is involved in this process? And thirdly, do MCs recruited juxtaposed to the epithelium by HPV16 E7 expression mediate local immune suppression?
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