Is Beta-HPV Linked to cSCC?

Nonmelanoma skin cancers, including cutaneous squamous cell carcinoma (cSCC), are among the most common cancers throughout the world. The prevailing view among scientists has been that human papillomavirus (HPV) is merely a facilitator in the accumulation of DNA mutations caused by ultraviolet radiation, which is typically the main driver of cSCC. However, researchers at the National Institutes of Health (NIH) have shown for the first time that beta (β)-HPV, which is commonly found on the skin, can be a direct cause of cSCC after certain immune cells malfunction. Their findings were published in a case report in The New England Journal of Medicine.

“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,” said senior report author Andrea Lisco, MD, PhD, of NIH’s National Institute of Allergy and Infectious Diseases, in an NIH press 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.”

Study Details

The NEJM case report describes a 34yearold immunocompromised woman seeking treatment for a cSCC on her forehead. The tumor had recurred despite multiple surgeries and a round of immunotherapy, leading her doctors to consider the possibility of a genetic inability to repair DNA damaged by UV radiation plus T-cell impairment. The patient had experienced several other worsening HPV-related diseases.

A sophisticated genetic analysis revealed that a β-HPV had integrated into the cellular DNA of the woman’s tumor and was producing extensive amounts of viral proteins there, contradicting the prevailing paradigm that β-HPV acts only as a passive cofactor rather than an oncogenic agent.

To understand this newly discovered phenomenon, the investigators studied the patient’s inherited immune disorder and found that her genetic mutations impeded her T cells from activating in response to the skin cell infection cause by β-HPV. This indicated that it was the immune disorder itself that was responsible for the woman’s worsening disease.

Treatment and Results

The patient underwent allogeneic hematopoietic stem cell transplantation to replace her defective T cells with healthy ones. After the transplant, which proceeded without complications, all of the woman’s HPV-related diseases—including the recurrent, aggressive cSCC—resolved and have not recurred as of more than 3 years since the treatment.

According to the study authors, these findings suggest that other people with defective T-cells may also be at risk for cancer caused directly by β-HPV.

They concluded, “The characterization of T-cell functions and β-HPV transcriptional activity in patients with recurrence of aggressive [cSCC] may be valuable in other clinical contexts in which boosting T-cell–based immunity against β-HPVs (eg, by therapeutic immunization or immune checkpoint inhibition) can be developed or further improved for the prevention and management of cSCC.”

Disclosure: For full disclosures of the study authors, visit nejm.org.

The New England Journal of Medicine