National Institutes of Health researchers found that beta-human papillomavirus can directly cause cutaneous squamous cell carcinoma in immunocompromised patients, with complete remission following immune system restoration.
A case study published in The New England Journal of Medicine described the complete resolution of recurrent, invasive cutaneous squamous cell carcinoma (SCC) and other beta-human papillomavirus (beta-HPV)–associated lesions in a 34-year-old woman with defective T-cell receptor (TCR) signaling due to compound heterozygous ZAP70 mutations. The findings challenge the long-standing view that beta-HPV is not essential for SCC maintenance and suggest a direct oncogenic role in the setting of immunodeficiency.
The patient presented with 43 biopsy-confirmed SCC lesions and widespread mucocutaneous HPV disease, including an unresectable, treatment-resistant SCC on the forehead. Histopathology demonstrated high-risk features such as perineural and vascular invasion.
Molecular analysis of the tumor revealed integration of beta1-HPV19 DNA into the tumor genome and high-level expression of E6/E7 oncogenes. The tumor lacked common SCC driver mutations (TP53, NOTCH1/2, CDKN2A) and had a low tumor mutational burden of 6 mutations per megabase—well below the typical approximately 50 per megabase for sporadic SCC. Ultraviolet (UV)-related mutational signatures were modest.
Genetic evaluation confirmed compound heterozygous ZAP70 variants and a homozygous RNF168 variant previously linked to impaired UV-DNA repair. However, functional assays demonstrated normal DNA damage responses, ruling out UV hypersensitivity as the primary. Immunologic studies highlighted severely impaired TCR signaling, reduced phosphorylation of downstream molecules (e.g., PLCγ1, ERK), and deficient T-cell proliferation and HPV-specific immune responses.
The patient underwent haploidentical hematopoietic cell transplantation to correct T-cell dysfunction. Post-transplant testing confirmed restored TCR signaling, improved T-cell proliferation, and robust HPV19-specific T-cell immune responses. All HPV-related lesions, including the previously refractory SCC, resolved and have not recurred for more than 3 years.
The authors noted that the case provides direct evidence that beta-HPV can act as an independent driver of skin cancer in the context of impaired T-cell–mediated immunity and highlight the importance of assessing immune function in patients with aggressive, treatment-resistant SCC.
The study was funded by the National Institutes of Health, and the authors reported no relevant conflicts of interest.
Sources: The New England Journal of Medicine, National Institutes of Health
