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Immunity to commensal papillomaviruses protects against skin cancer.

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 (?-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 ?-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 ?-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.

SUBMITTER: Strickley JD

PROVIDER: S-EPMC6872936 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Immunity to commensal papillomaviruses protects against skin cancer.

Strickley John D JD Messerschmidt Jonathan L JL Awad Mary E ME Li Tiancheng T Hasegawa Tatsuya T Ha Dat Thinh DT Nabeta Henry W HW Bevins Paul A PA Ngo Kenneth H KH Asgari Maryam M MM Nazarian Rosalynn M RM Neel Victor A VA Jenson Alfred Bennett AB Joh Joongho J Demehri Shadmehr S

Nature 20191030 7783

Immunosuppression increases the risk of cancers that are associated with viral infection<sup>1</sup>. 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 patients<sup>2-4</sup>. 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 suppr ...[more]

PMID: 31666702

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Project description:Staphylococcus hominis is frequently isolated from human skin, and we hypothesize that it may protect the cutaneous barrier from opportunistic pathogens. We determined that S. hominis makes six unique autoinducing peptide (AIP) signals that inhibit the major virulence factor accessory gene regulator (agr) quorum sensing system of Staphylococcus aureus. We solved and confirmed the structures of three novel AIP signals in conditioned medium by mass spectrometry and then validated synthetic AIP activity against all S. aureus agr classes. Synthetic AIPs also inhibited the conserved agr system in a related species, Staphylococcus epidermidis. We determined the distribution of S. hominis agr types on healthy human skin and found S. hominis agr-I and agr-II were highly represented across subjects. Further, synthetic AIP-II was protective in vivo against S. aureus-associated dermonecrotic or epicutaneous injury. Together, these findings demonstrate that a ubiquitous colonizer of human skin has a fundamentally protective role against opportunistic damage. IMPORTANCE Human skin is home to a variety of commensal bacteria, including many species of coagulase-negative staphylococci (CoNS). While it is well established that the microbiota as a whole maintains skin homeostasis and excludes pathogens (i.e., colonization resistance), relatively little is known about the unique contributions of individual CoNS species to these interactions. Staphylococcus hominis is the second most frequently isolated CoNS from healthy skin, and there is emerging evidence to suggest that it may play an important role in excluding pathogens, including Staphylococcus aureus, from colonizing or infecting the skin. Here, we identified that S. hominis makes 6 unique peptide inhibitors of the S. aureus global virulence factor regulation system (agr). Additionally, we found that one of these peptides can prevent topical or necrotic S. aureus skin injury in a mouse model. Our results demonstrate a specific and broadly protective role for this ubiquitous, yet underappreciated skin commensal.

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Immunity to commensal papillomaviruses protects against skin cancer.

Publications

Immunity to commensal papillomaviruses protects against skin cancer.

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