Mus musculus papillomavirus 1 is a key driver of skin cancer development upon immunosuppression

Skin Cancer
20/10/2020

Am J Transplant. 2020 Oct 15. doi: 10.1111/ajt.16358. Online ahead of print.

ABSTRACT

Epidemiological and experimental data implicate cutaneous human papillomavirus infection as co-factor in the development of cutaneous squamous cell carcinomas (cSCCs), particularly in immunocompromised organ transplant recipients (OTRs). Herein, we established and characterized a skin cancer model, in which Mus musculus papillomavirus 1 (MmuPV1) infection caused cSCCs in cyclosporine A (CsA)-treated mice, even in the absence of UV-light. Development of cSCCs and their precursors were observed in


70% of MmuPV1-infected, CsA-treated mice on back as well as tail skin. Immunosuppression by systemic CsA, but not UV-B irradiation, was a prerequisite, as immunocompetent or UV-B-irradiated mice did not develop skin malignancies after infection. In the virus-driven cSCCs the MmuPV1-E6/E7 oncogenes were abundantly expressed, and transcriptional activity and productive infection demonstrated. MmuPV1 infection induced expression of phosphorylated H2AX, but not degradation of pro-apoptotic BAK in the cSCCs. Transfer of primary cells, established from a MmuPV1-induced cSCC from back skin, into athymic nude mice gave rise to secondary cSCCs, which lacked viral DNA, demonstrating that maintenance of the malignant phenotype was virus-independent. This papillomavirus-induced skin cancer model opens future investigations into viral involvement, pathogenesis and cancer surveillance, aiming at understanding and controlling the high incidence of skin cancer in OTRs.