Immunity to commensal papillomaviruses protects against skin cancer.

Abstract

Immunosuppression increases the risk of cancers associated with viral infection1. In particular, squamous cell carcinoma (SCC) of the skin has a >100-fold increased risk in immunosuppressed patients and has been associated with beta human papillomavirus (β-HPV) infection2–4. Previous studies, however, have failed to establish a causative role for HPVs in driving skin cancer development. Herein, we provide an alternative explanation for this association by demonstrating that the T cell immunity against commensal papillomaviruses suppresses skin cancer in immunocompetent hosts. The loss of this immunity, rather than the oncogenic effect of HPVs, is the reason for the markedly increased risk of skin cancer in immunosuppressed patients. To investigate the impact of papillomavirus on carcinogen-driven skin cancer, we colonized several strains of immunocompetent mice with mouse papillomavirus type 1 (MmuPV1)5. Mice with natural anti-MmuPV1 immunity after colonization and acquired immunity due to T cell transfer from immune mice or MmuPV1 vaccination were protected against chemical- and ultraviolet (UV)-induced skin carcinogenesis in a CD8+ T cell-dependent manner. RNA and DNA in situ hybridizations for 25 commensal β-HPVs revealed a significant reduction in viral activity and load in human skin cancer compared to the adjacent normal skin, suggesting a strong immune selection against virus-positive malignant cells. Consistently, β-HPV E7 peptides activated CD8+ T cells from normal human skin. Our findings reveal a beneficial role for commensal viruses and establish the foundation for novel immune-based approaches to block skin cancer development by boosting immunity against the commensal HPVs present in all of our skin.