Enhanced Spontaneous Skin Tumorigenesis and Aberrant Inflammatory Response to UVB Exposure in Immunosuppressed HPV8 Transgenic Mice

Human papillomaviruses (HPVs) from the beta genus are commensal viruses of the skin usually associated with asymptomatic infection in the general population. However, in individuals with specific genetic backgrounds, such as epidermodysplasia verruciformis patients, or those with immune defects, such as organ transplant recipients (OTRs), they are functionally involved in sunlight-induced skin cancer development, mainly keratinocyte carcinoma. Despite their well-established protumorigenic role, the cooperation between β-HPV infection, impaired host immunosurveillance, and UVB exposure has never been formally demonstrated in animal models. Here, by crossing skin-specific HPV8 transgenic mice with Rag2-deficient mice, we have generated a pre-clinical mouse model, named Rag2-/-:K14-HPV8. These mice display an unhealthy skin phenotype and spontaneously develop papilloma-like lesions spreading to the entire skin much more rapidly compared to Rag2+/+:K14-HPV8 mice. Exposure to low-doses of UVB radiation is sufficient to trigger severe skin inflammation in Rag2-/-:K14-HPV8 but not Rag2+/+:K14-HPV8 mice. Their inflamed skin very much resembled that observed in cutaneous field cancerization in OTRs, showing high levels of UVB-damaged cells, enhanced production of pro-inflammatory cytokines, and mast cell recruitment to the dermis. Overall, this immunocompromised HPV8 transgenic mouse model demonstrates that the coexistence of immune defects, β-HPV, and UVB exposure promotes skin cancer development.