Immunity to commensal papillomaviruses protects against skin cancer

Nature. 2019 Nov;575(7783):519-522. doi: 10.1038/s41586-019-1719-9. Epub 2019 Oct 30.


Immunosuppression increases the risk of cancers that are associated with viral infection1. In particular, the risk of squamous cell carcinoma of the skin-which has been associated with beta human papillomavirus (β-HPV) infection-is increased by more than 100-fold in immunosuppressed patients2-4. Previous studies have not established a causative role for HPVs in driving the development of skin cancer. Here we show that T cell immunity against commensal papillomaviruses suppresses skin cancer in immunocompetent hosts, and the loss of this immunity-rather than the oncogenic effect of HPVs-causes the markedly increased risk of skin cancer in immunosuppressed patients. To investigate the effects of papillomavirus on carcinogen-driven skin cancer, we colonized several strains of immunocompetent mice with mouse papillomavirus type 1 (MmuPV1)5. Mice with natural immunity against MmuPV1 after colonization and acquired immunity through the transfer of T cells from immune mice or by MmuPV1 vaccination were protected against skin carcinogenesis induced by chemicals or by ultraviolet radiation in a manner dependent on CD8+ T cells. RNA and DNA in situ hybridization probes for 25 commensal β-HPVs revealed a significant reduction in viral activity and load in human skin cancer compared with the adjacent healthy skin, suggesting a strong immune selection against virus-positive malignant cells. Consistently, E7 peptides from β-HPVs activated CD8+ T cells from unaffected human skin. Our findings reveal a beneficial role for commensal viruses and establish a foundation for immune-based approaches that could block the development of skin cancer by boosting immunity against the commensal HPVs present in all of our skin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinogenesis / radiation effects
  • Carcinoma, Squamous Cell / immunology*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / prevention & control*
  • Carcinoma, Squamous Cell / virology
  • Female
  • Humans
  • Immunocompromised Host / immunology
  • Male
  • Mice
  • Middle Aged
  • Oncogenes
  • Papillomaviridae / genetics
  • Papillomaviridae / immunology*
  • Papillomaviridae / pathogenicity
  • Papillomavirus Infections / immunology*
  • Papillomavirus Infections / virology*
  • RNA, Viral / analysis
  • RNA, Viral / genetics
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • Skin Neoplasms / prevention & control*
  • Skin Neoplasms / virology*
  • Symbiosis*
  • Ultraviolet Rays


  • RNA, Viral