The most common cancer-causing strain of human papillomavirus (HPV), HPV16, undermines the body’s defenses by reprogramming immune cells surrounding the tumor, according to new USC research. In mice, blocking this process boosted the ability of experimental treatments for HPV to eliminate cancer cells. HPV16 causes more than half of cervical cancer cases and roughly 90% of HPV-linked throat cancers. It can be neutralized with the preventive vaccine Gardasil-9, but only if vaccination occurs prior to HPV exposure. Researchers are now working to develop “therapeutic vaccines,” which can be taken after HPV exposure to trigger an immune response by T-cells against infected cells, but in clinical trials, these vaccines have limited effectiveness—and the new study helps explain why. The study focuses on the signaling protein Interleukin-23 or IL-23 in the immune system which has inflammatory properties. While IL-23 was previously implicated in cervical and throat cancers, its exact role was unclear. In a series of tests in mice and cell cultures, USC researchers found that two HPV proteins, E6 and E7, prompt nearby cells to release IL-23, which in turns prevents the body’s T-cells from attacking the tumor. In mice with HPV16 tumors, IL-23 neutralizing antibodies blocked IL-23 and increased the number of T-cells around the tumor that could recognize and kill cancer. When combined with the HPV therapeutic vaccine, this approach triggered a stronger immune response and led to longer survival than either treatment on its own.