The HPV16 E7 Oncoprotein Disrupts Dendritic Cell Function and Induces the Systemic Expansion of CD11b⁺Gr1⁺Cells in a Transgenic Mouse Model

Abstract

Objective. The aim of this study was to analyze the effects of the HPV16 E7 oncoprotein on dendritic cells (DCs) and CD11b+Gr1+ cells using the K14E7 transgenic mouse model. Materials and Methods. The morphology of DCs was analyzed in male mouse skin on epidermal sheets using immunofluorescence and confocal microscopy. Flow cytometry was used to determine the percentages of DCs and CD11b+Gr1+ cells in different tissues and to evaluate the migration of DCs. Results. In the K14E7 mouse model, the morphology of Langerhans cells and the migratory activity of dendritic cells were abnormal. An increase in CD11b+Gr1+ cells was observed in the blood and skin of K14E7 mice, and molecules related to CD11b+Gr1+ chemoattraction (MCP1 and S100A9) were upregulated. Conclusions. These data suggest that the HPV16 E7 oncoprotein impairs the function and morphology of DCs and induces the systemic accumulation of CD11b+Gr1+ cells.

Recent advances in preclinical model systems for papillomaviruses

“…Initial work with a transgenic mouse model containing BPV-1 and HPV-5 and HPV-18 showed the development of skin lesions and viral amplification in situ in mice with BPV-1 genomes (Kondoh, Li et al, 1995; Hanahan, Wetzel et al, 1989). Several transgenic mouse models expressing HPV viral oncogenes in cutaneous tissues have also been studied extensively (Thomas, Pitot et al, 2011; Damian-Morales, Serafin-Higuera et al, 2016; Griep, Herber et al, 1993; Akgul, Pfefferle et al, 2006; Schaper, Marcuzzi et al, 2005). Important discoveries have accrued from these models on the impact of viral oncogenes in vivo, and at important anatomic sites such as the cervix and anal epithelium (Spurgeon, Chung et al, 2014; Thomas, Pitot et al, 2011).…”

Vitamin A deficiency in K14E7HPV expressing transgenic mice facilitates the formation of malignant cervical lesions

“…Another consistent feature from our study was the finding of extensive mononuclear inflammatory infiltrate in cervical tissue of both VAD transgenic mice. In agreement with this observation, it was found that depletion of retinoids or the alteration of their nuclear receptors can affect different cellular populations involved in inflammation and immune system evasion of diverse compartments such as spleen, intestine, or eyes [21,27]; for example, increased percent of systemic CD11b+Gr1+ cells found in SENCAR mice [28], as well as in K14E7 mice [29]. Indeed, chronic inflammation has been associated with epithelial cancers and cells with CD11b+Gr1+ phenotype have been found in tumor microenvironment [30].…”

Nanobody–Antigen Conjugates Elicit HPV-Specific Antitumor Immune Responses

“…CD11b + cells have been observed in the skin of transgenic K14E7 mice that constitutively express E7 in squamous epithelium (33). Therefore, we utilized VHH CD11b as an immunoPET imaging agent in C3.43 tumor-bearing mice to test for the presence of intratumoral CD11b + cells.…”

“…E7 expression in the skin of mice results in expansion of CD11b + cells (33). In particular, more CD11b + Gr1 + cells were present in the skin of transgenic K14E7 mice (33), which constitutively express HPV16 E7 in squamous epithelium (45). CD11b + Gr1 + cells are defined as myeloid-derived suppressor cells (MDSCs) that can show intratumoral immunosuppressive activity (46).…”