Beta-human papillomavirus (beta-HPV) can directly cause cutaneous squamous cell carcinoma (cSCC), National Institutes of Health (NIH) report.

Found mostly on the skin, beta-HPV are considered benign members of the skin microbiome that typically do not integrate into the DNA of skin cells. This contrasts with the alpha types of HPV, known to integrate into the DNA of mucous membrane cells and directly cause cancer of the genitals, anus, head, and neck. Previously, scientists believed HPV merely facilitated the accumulation of DNA mutations caused by ultraviolet (UV) radiation, usually the primary driver of cSCC.

“This discovery could completely change how we think about the development, and consequently the treatment, of cSCC in people who have a health condition that compromises immune function,” says Andrea Lisco, MD, PhD, of NIH’s National Institute of Allergy and Infectious Diseases (NIAID), in a news release. “It suggests that there may be more people out there with aggressive forms of cSCC who have an underlying immune defect and could benefit from treatments targeting the immune system.”

Case Study of a 34-year-old Woman With cSCC

The NIH researchers made their discovery in a 34-year-old woman who came to the NIH Clinical Center for evaluation and treatment of recurrent cSCC on her forehead. She had undergone multiple surgeries and a round of immunotherapy to try to remove or kill the tumor, but it repeatedly grew back. Her local doctors thought this was due to an inherited inability to repair DNA damaged by UV radiation plus an impairment in immune cells called T cells. The tumor was one of many progressively worsening HPV-related diseases the woman was experiencing.

Through a sophisticated genetic analysis, the NIH researchers discovered that beta-HPV had integrated into the cellular DNA of the woman’s well-established tumor and was extensively producing viral proteins there. This contradicted the prevailing theory that beta-HPV only facilitates the establishment of cSCC without integrating into cellular DNA and plays no role in maintaining the cancer.

Further genetic analysis of the woman’s cells showed they were fully capable of repairing DNA damage from UV radiation, suggesting the virus alone had caused cSCC.

Further Study of Immune Disorder

To understand how beta-HPV could integrate into the woman’s skin-cell DNA and multiply there unchecked, the investigators studied the woman’s inherited immune disorder. They found that her genetic mutations greatly hampered T cells from activating in response to skin-cell infection by beta-HPV. This suggested that the immune disorder itself was responsible for the woman’s worsening HPV-related diseases, including the beta-HPV cSCC on her forehead, and that treating this disorder might cure all of them.

Accordingly, NIH investigators developed a personalized plan to give the woman a stem cell transplant to replace her defective T cells with healthy ones. The process required extreme care because she was immunocompromised even before treatment began. The transplant proceeded without complications. Afterward, all her HPV-related diseases—including the recurrent, aggressive cSCC—resolved and have not recurred during the more than three years since the transplant. This confirms that the woman’s inherited disorder had prevented her T cells from keeping beta-HPV in check, allowing the virus to directly cause and sustain cSCC.

The finding suggests that other people with defective T-cell responses may also be susceptible to cancer caused directly by beta-HPV, the study authors note.

The case report is published in The New England Journal of Medicine.