Scientists at Henry Ford Health and Michigan State University Health Sciences announced on Mar. 18 the discovery of a protein that allows certain head and neck cancers linked to Human Papillomavirus (HPV) to avoid detection by the immune system. The findings, published in Proceedings of the National Academy of Sciences, show that blocking this protein could make previously resistant tumors responsive to treatment.
This research is significant because some HPV-associated cancers lack molecular markers called MHCI molecules, which are necessary for the immune system to recognize and attack abnormal cells. Without these markers, the immune system does not detect the cancer, making it difficult to treat with standard therapies.
The team led by Dohun Pyeon, Ph.D., found that HPV uses a protein called MARCHF8 to remove these MHCI markers from cancer cells. When researchers removed MARCHF8 in experimental models, immune cells such as CD8+ T cells and natural killer cells were able to enter the tumor environment and clear the tumors—even those unresponsive to previous immunotherapy treatments. "The most exciting part is that our discovery worked on tumors that were previously impossible to treat," said Pyeon. He added, "By combining this new genetic approach with standard immunotherapy drugs, we were able to turn 'cold' tumors that typically ignore treatment into 'hot' tumors where the immune system can prevail. This suggests that in the future, we might be able to help patients who currently have no other options by simply stopping the cancer from shredding its red flags."
Mohamed Khalil, Ph.D., first author of the study, explained how removing MARCHF8 not only slowed tumor growth but also improved anti-tumor immune responses. "We found that the MARCHF8 knockout activated T cells and enhanced T cells, natural killer cells, and macrophage infiltration into the tumor microenvironment," said Khalil. "I think we have very promising hope for targeting MARCHF8."
Qing-Sheng Mi, M.D., Ph.D., co-principal investigator on this project and director of several programs at Henry Ford Health and MSU College of Human Medicine, used single-cell RNA-sequencing technology to analyze how knocking out MARCHF8 changed interactions between immune cells within tumors. "We showed knocking out MARCHF8 fundamentally rewires immune cell crosstalk - dramatically boosting the cytotoxic activity of CD8+ T cells and NK cells," said Mi. "It revealed not just that the therapy works, but precisely how and why." Mi also said: "This could restore the immune system's ability to recognize and destroy these tumors in combination with existing immunotherapies."
The next step for researchers is developing a drug that blocks MARCHF8 in humans so doctors can combine it with current immunotherapies for patients whose cancers resist all other treatments.
Last year’s work was supported by a $3 million grant from the National Institute of Dental and Craniofacial Research as well as funding from an MSU Foundation Strategic Partnership grant and Henry Ford + MSU Cancer Seed Funding Program.
