Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin

Heehwa G Son; Dat Thinh Ha; Yun Xia; Tiancheng Li; Jasmine Blandin; Tomonori Oka; Marjan Azin; Danielle N Conrad; Can Zhou; Yuhan Zeng; Tatsuya Hasegawa; John D Strickley; Jonathan L Messerschmidt; Ranya Guennoun; Tal H Erlich; Gregory L Shoemaker; Luke H Johnson; Kenneth E Palmer; David E Fisher; Thomas D Horn; Victor A Neel; Rosalynn M Nazarian; Joongho J Joh; Shadmehr Demehri

doi:10.1016/j.ccell.2024.11.013

Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin

Cancer Cell. 2024 Dec 7:S1535-6108(24)00448-3. doi: 10.1016/j.ccell.2024.11.013. Online ahead of print.

Authors

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: [email protected].

PMID: 39672169
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.