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 research from the Keck School of Medicine of USC. In mice, blocking this process boosted the ability of experimental treatments for HPV to eliminate cancer cells. The results were just published in the Journal for ImmunoTherapy of Cancer .
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—for instance, following an abnormal pap smear or cancer diagnosis—to trigger an immune response against infected cells by T-cells, a type of "fighter" cell that helps defend the body from disease. But these vaccines, now in clinical trials, have limited effectiveness—and the new study helps explain why.
The research, funded in part by the National Institutes of Health, focuses on a signaling protein in the immune system with inflammatory properties called Interleukin-23 or IL-23. 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 order to eliminate the cancer, T-cells need to proliferate and destroy infected cells. But IL-23 stops them from working effectively, so the tumor keeps growing," said the study's senior author, W. Martin Kast, PhD , professor of molecular microbiology & immunology, obstetrics & gynecology, and otolaryngology and Walter A. Richter Cancer Research Chair at the Keck School of Medicine.
Kast and his colleagues found that blocking IL-23 made an HPV therapeutic vaccine more effective because it let T-cells do their job: find and kill cancer. Antibodies that inhibit IL-23 are already FDA-approved for treating psoriasis and other conditions, offering a clear and potentially quick path to use in cancer treatment when they are combined with therapeutic vaccines.
"The fact that these antibodies are already FDA-approved for something else makes this approach promising—and it also allows for rapid translation into the clinic," said Kast, who also co-leads the Tumor Microenvironment Program at the USC Norris Comprehensive Cancer Center.
The role of IL-23
Researchers used a combination of cell cultures, mouse studies and genomic analyses to uncover IL-23's role in cancers caused by HPV16.
First, they implanted mice with HPV16 tumors, then delivered a therapeutic vaccine that caused the mice to develop specialized T-cells for fighting the tumor. They extracted these T-cells, then combined them with IL-23. When IL-23 was present, the T-cells had reduced capacity to multiply and destroy cancerous cells.
The researchers then gave IL-23 neutralizing antibodies to mice with HPV16 tumors. Blocking IL-23 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.
Researchers also analyzed the RNA and chromatin (the DNA and proteins that control gene activity) of tumor cells to reveal precisely how HPV's E6 and E7 proteins increase IL-23 production. Understanding the biological mechanism is a key step toward better treatments for HPV-linked cancers, Kast said.
New strategies for treatment
The study offers insight into why therapeutic vaccines for HPV, now in clinical trials, have had limited success.
"Therapeutic vaccines do prompt the immune system to create HPV-specific T-cells, but they don't work well—and now we have an idea why," Kast said.
Combining experimental vaccines with IL-23 neutralizing antibodies could significantly increase their effectiveness, he added. He and his team are now developing their own therapeutic vaccine, which they will test in combination with antibodies that block IL-23.
The findings may have implications for cancers not related to HPV, such as testicular and bladder cancers, where IL-23 is also found at high levels. Further research is needed to clarify what role IL-23 plays in those diseases, the researchers said.
About this research
In addition to Kast, the study's other authors are Ruben Prins, Daniel Fernandez and Omid Akbari from the Department of Molecular Microbiology and Immunology and the USC Norris Comprehensive Cancer Center, Keck School of Medicine of USC, University of Southern California; and Diane Da Silva from the Department of Obstetrics & Gynecology and the USC Norris Comprehensive Cancer Center, Keck School of Medicine of USC, University of Southern California.
This work was supported by the National Institutes of Health [R01 CA074397], the American Association of Immunologists, R.F. Brennan, S. Bloch and I.Y. Khandros.
