Papillomavirus-associated squamous skin cancers following transplant immunosuppression: one Notch closer to control

Area of Science:

• Dermatology
• Oncology
• Virology

Background:

• Cutaneous squamous cell carcinomas (SCCs) are common in organ transplant recipients, often associated with human papillomaviruses (HPVs).
• The precise mechanisms linking immunosuppression, HPV, and SCC development remain incompletely understood.
• Recent findings illuminate the roles of specific HPV types, genetic syndromes, and therapeutic interventions in SCC pathogenesis.

Purpose of the Study:

• To elucidate the complex interplay between iatrogenic immunosuppression, human papillomaviruses (HPVs), and the development of cutaneous squamous cell carcinomas (SCCs).
• To integrate recent insights into HPV associations, immunosuppressive drug effects, and tumor microenvironment signaling in SCC pathogenesis.
• To inform reappraisal of management strategies for skin SCCs in transplant patients.

Main Methods:

• Review and synthesis of recent findings on HPV-beta (β) and HPV-alpha (α) types in SCCs.
• Analysis of the impact of immunosuppressive agents (calcineurin inhibitors, mTOR inhibitors) on tumor control.
• Investigation of the role of UV radiation, TP53 mutations, and Notch signaling in SCC development.

Main Results:

• Low-risk β-HPVs are associated with SCCs in genetic syndromes; high-risk α-HPVs in oropharyngeal SCCs have a favorable prognosis.
• Substitution of calcineurin inhibitors with mTOR inhibitors often improves post-transplant tumor control.
• β-HPV E6 oncoproteins inhibit Notch signaling, potentially exacerbating SCC development in conjunction with UV damage and immunosuppression.

Conclusions:

• A complex interplay exists between UV-induced mutations, impaired immunity, and β-HPV-driven signaling in skin SCCs.
• Calcineurin inhibitors may intensify mitogenic signaling in TP53-mutant keratinocytes and reduce immune-mediated tumor repression.
• Reappraising management strategies for skin SCCs in transplant patients is timely given these insights.