Immunity to commensal papillomaviruses protects against skin cancer

John D. Strickley, Jonathan L. Messerschmidt, Mary E. Awad, Tiancheng Li, Tatsuya Hasegawa, Dat Thinh Ha, Henry W. Nabeta, Paul A. Bevins, Kenneth H. Ngo, Maryam M. Asgari, Rosalynn M. Nazarian, Victor A. Neel, Alfred Bennett Jenson, Joongho Joh and Shadmehr Demehri ()
Additional contact information
John D. Strickley: Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School
Jonathan L. Messerschmidt: Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School
Mary E. Awad: Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School
Tiancheng Li: Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School
Tatsuya Hasegawa: Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School
Dat Thinh Ha: Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School
Henry W. Nabeta: University of Louisville
Paul A. Bevins: Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School
Kenneth H. Ngo: Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School
Maryam M. Asgari: Massachusetts General Hospital and Harvard Medical School
Rosalynn M. Nazarian: Massachusetts General Hospital and Harvard Medical School
Victor A. Neel: Massachusetts General Hospital and Harvard Medical School
Alfred Bennett Jenson: University of Louisville
Joongho Joh: University of Louisville
Shadmehr Demehri: Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School

Nature, 2019, vol. 575, issue 7783, 519-522

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1719-9

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