Research Spotlight: Interplay Between Immune Cells and HPV Keeps Skin Healthy

Shadmehr (Shawn) Demehri, MD, PhD, of the Department of Dermatology and Center for Cancer Immunology at Massachusetts General Hospital, is the corresponding author of a paper published in Cancer Cell, “Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin.”

How would you summarize your study for a lay audience? 

Sun-damaged normal skin contains many mutations caused by ultraviolet (UV) radiation. However, the mechanism by which sun-damaged skin maintains its normal function and the role of the immune system in this maintenance is unknown. In this study, we find that human papillomaviruses (HPV) residing in the skin help virus-specific immune cells detect and suppress the expansion of mutant skin cells, thereby promoting the normal state of the skin exposed to UV. We found that papillomavirus activity is specifically increased in the mutated skin cells, effectively tagging them for destruction by killer T cells. Our findings highlight the importance of the immune response to commensal HPVs in maintaining healthy skin as we age. Thus, boosting anti-HPV T cells can further protect the skin from cancer.

What question were you investigating?

There are more than 200 types of HPV, which can infect skin or mucosal tissues. While some high-risk α-HPV types can infect mucosal tissues and cause cancers, like cervical cancer, others (β- and γ-HPVs) are commonly found in humans and do not cause disease in immunocompromised individuals. We previously demonstrated that skin-residing HPVs can protect the skin against skin cancer caused by carcinogens, such as ultraviolet (UV) radiation. In this study, we aimed to determine how papillomavirus skin colonization leads to improved homeostasis of sun-damaged skin and what the role of virus-specific immune response is in this protection. We found that CD8+ T cells specifically infiltrate mutant clones in papillomavirus-infected skin. This raised the question of how papillomavirus-induced T cells selectively target mutant clones without affecting unmutated normal cells.

What approach did you use?

To explore this, we studied the interaction between the virus and the main mutation caused by UV, p53 mutation using experimental models and human tissue samples.

What did you find?

We found that UV-induced p53 loss of function mutations lead to increased viral levels in the mutant cells, tagging them for destruction by T cells. Further investigation showed that papillomavirus colonization of the skin helps maintain skin health after UV damage. Papillomavirus-specific T cells prevent the growth of UV-mutated cells, revealing the beneficial role of the human virome and immune response in promoting the health of virus-colonized tissues as we age.

What did you find?

In the elderly and organ transplant recipients, weakened immune responses to HPV in the skin increase the risk of actinic keratosis (AK) and skin cancer. Our findings reveal an innovative therapeutic strategy that promotes anti-HPV T cell immunity in the skin to maintain healthy skin and prevent cancer. Our work lays the foundation to leverage the human virome and immunity toward it to promote health and prevent disease.


What are the implications?

In the elderly and organ transplant recipients, weakened immune responses to HPV in the skin increase the risk of actinic keratosis (AK) and skin cancer. Our findings reveal an innovative therapeutic strategy that promotes anti-HPV T cell immunity in the skin to maintain healthy skin and prevent cancer. Our work lays the foundation to leverage the human virome and immunity toward it to promote health and prevent disease.

What are the next steps?

We are actively pursuing the therapeutic implications of our fundamental findings. We are investigating novel treatments that can boost anti-HPV T cell immunity in the skin to help prevent skin cancer in elderly and immunosuppressed patients. In addition, we are exploring the beneficial role of other eukaryotic DNA viruses that ubiquitously live in humans in regulating the immune response in the tissues that they colonize. These efforts will enable us to leverage the human virome to promote health and prevent disease.

Authorship: In addition to Demehri, MGB authors include 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, David E. Fisher, Thomas D. Horn, Victor A. Neel and Rosalynn M. Nazarian.

Paper cited: Son H et al. “Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin.” Cancer Cell 

Funding: Demehri holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund and was supported by LEO Foundation Award LF-AW_RAM-22-400154. Son was supported by the National Research Foundation of Korea (2021R1A6A3A03040237) and MGH Fund for Medical Discovery (2023A072200). Xia was supported by Cancer Research Institute Irvington Postdoctoral Fellowship. Li was supported by the China Scholarship Council and the Department of Otorhinolaryngology–Head and Neck Surgery, Peking University First Hospital, Beijing, China. Oka was supported by the Japan Society for the Promotion of Science and The Uehara Memorial Foundation. Horn was supported by Shiseido Co. Ltd. Fisher gratefully acknowledges support to his laboratory from NIH grants P01 CA163222, R01 AR072304, and R01 AR043369, as well as funding from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Melanoma Research Alliance. Son, Ha, Xia, Li, Blandin, Oka, Azin, Conrad, Hasegawa, Strickley, Messerschmidt, Guennoun, Johnson, Joh, and Demehri were supported by grants from the Burroughs Wellcome Fund and NIH (R01 CA251755 and R01 AR076013).

Disclosures: Fisher 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. Demehri is an inventor on a filed patent for the development of T cell-directed anti-cancer vaccines against commensal viruses (PCT/US2019/063172). Other authors declare no conflict of interest. The interests of Fisher and Demehri are reviewed and managed by Massachusetts General Hospital and Mass General Brigham HealthCare in accordance with their conflict-of-interest policies.