Resolution of Squamous-Cell Carcinoma by Restoring T-Cell Receptor Signaling

Cutaneous squamous-cell carcinoma (SCC) is primarily caused by oncogenesis mediated by ultraviolet radiation, and β-human papillomavirus (β-HPV) is believed to be a mere facilitator that is dispensable for the maintenance of cutaneous SCC. Here, we describe a woman with benign and malignant HPV-related diseases that include a recurrent, unresectable, invasive cutaneous SCC with β-HPV19 genomic integration in the context of germline pathogenic mutations in ZAP70, an adapter required for T-cell receptor (TCR) signal transduction. Restoration of the integrity of TCR signaling by allogeneic hematopoietic-cell transplantation led to the resolution of all HPV-related diseases, thereby revealing a direct role of β-HPV in skin carcinogenesis in hosts with defective adaptive T-cell responses. (Funded by the National Institutes of Health.).