. 2025 Jan 13;43(1):36-48.e10.

doi: 10.1016/j.ccell.2024.11.013. Epub 2024 Dec 12.

Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin

Heehwa G Son¹, Dat Thinh Ha², Yun Xia¹, Tiancheng Li¹, Jasmine Blandin¹, Tomonori Oka¹, Marjan Azin¹, Danielle N Conrad¹, Can Zhou¹, Yuhan Zeng¹, Tatsuya Hasegawa¹, John D Strickley², Jonathan L Messerschmidt¹, Ranya Guennoun¹, Tal H Erlich³, Gregory L Shoemaker⁴, Luke H Johnson⁴, Kenneth E Palmer⁵, David E Fisher⁶, Thomas D Horn⁷, Victor A Neel⁷, Rosalynn M Nazarian⁸, Joongho J Joh⁹, Shadmehr Demehri¹⁰

Affiliations

¹ Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
³ Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA; Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY, USA.
⁵ Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; Center for Predictive Medicine, University of Louisville Health Sciences Center, Louisville, KY, USA.
⁶ Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁸ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA; Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY, USA.
¹⁰ Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: sdemehri1@mgh.harvard.edu.

PMID: 39672169
PMCID: PMC11732714 (available on 2026-01-13)
DOI: 10.1016/j.ccell.2024.11.013

Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin

Heehwa G Son et al. Cancer Cell. 2025.

. 2025 Jan 13;43(1):36-48.e10.

doi: 10.1016/j.ccell.2024.11.013. Epub 2024 Dec 12.

Authors

Affiliations

¹ Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
³ Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA; Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY, USA.
⁵ Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; Center for Predictive Medicine, University of Louisville Health Sciences Center, Louisville, KY, USA.
⁶ Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁸ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA; Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY, USA.
¹⁰ Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: sdemehri1@mgh.harvard.edu.

PMID: 39672169
PMCID: PMC11732714 (available on 2026-01-13)
DOI: 10.1016/j.ccell.2024.11.013

Abstract

Immunosuppression commonly disrupts the homeostasis of mutated normal skin, leading to widespread skin dysplasia and field cancerization. However, the immune system's role in maintaining the normal state of mutated tissues remains uncertain. Herein, we demonstrate that T cell immunity to cutaneotropic papillomaviruses promotes the homeostasis of ultraviolet radiation-damaged skin. Mouse papillomavirus (MmuPV1) colonization blocks the expansion of mutant p53 clones in the epidermis in a CD8⁺ T cell-dependent manner. MmuPV1 activity is increased in p53-deficient keratinocytes, leading to their specific targeting by CD8⁺ T cells in the skin. Sun-exposed human skin containing mutant p53 clones shows increased epidermal beta-human papillomavirus (β-HPV) activity and CD8⁺ T cell infiltrates compared with sun-protected skin. The expansion of mutant p53 clones in premalignant skin lesions associates with β-HPV loss. Thus, immunity to commensal HPVs contributes to the homeostasis of mutated normal skin, highlighting the role of virome-immune system interactions in preserving aging human tissues.

Keywords: CD8(+) T cell immunity; aging skin; clonal mutation; cutaneotropic papillomavirus; virome.

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Conflict of interest statement

Declaration of interests D.E.F. has a financial interest in Soltego, a company developing salt inducible kinase inhibitors for topical skin-darkening treatments that might be used for a broad set of human applications. S.D. is an inventor on a filed patent for the development of T cell-directed anti-cancer vaccines against commensal viruses (PCT/US2019/063172). The interests of D.E.F. and S.D. are reviewed and managed by Massachusetts General Hospital and Mass General Brigham HealthCare in accordance with their conflict-of-interest policies.

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References

1. Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S, Wedge DC, Fullam A, Alexandrov LB, Tubio JM, et al. (2015). Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886. 10.1126/science.aaa6806. - DOI - PMC - PubMed
1. Martincorena I, Fowler JC, Wabik A, Lawson ARJ, Abascal F, Hall MWJ, Cagan A, Murai K, Mahbubani K, Stratton MR, et al. (2018). Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917. 10.1126/science.aau3879. - DOI - PMC - PubMed
1. Yizhak K, Aguet F, Kim J, Hess JM, Kübler K, Grimsby J, Frazer R, Zhang H, Haradhvala NJ, Rosebrock D, et al. (2019). RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 364, eaaw0726. 10.1126/science.aaw0726. - DOI - PMC - PubMed
1. Yoshida K, Gowers KHC, Lee-Six H, Chandrasekharan DP, Coorens T, Maughan EF, Beal K, Menzies A, Millar FR, Anderson E, et al. (2020). Tobacco smoking and somatic mutations in human bronchial epithelium. Nature 578, 266–272. 10.1038/s41586-020-1961-1. - DOI - PMC - PubMed
1. Lee-Six H, Olafsson S, Ellis P, Osborne RJ, Sanders MA, Moore L, Georgakopoulos N, Torrente F, Noorani A, Goddard M, et al. (2019). The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537. 10.1038/s41586-019-1672-7. - DOI - PubMed

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Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin

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Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin

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