A New Target for Oral Cancer Treatment
For the first time, researchers have found evidence that the aryl hydrocarbon receptor regulates immune responses in oral squamous cell carcinoma, paving the way for new approaches to cancer prevention and treatment.
A new School of Public Health study has identified for the first time that the aryl hydrocarbon receptor (AhR), a protein that mediates the adverse effects of several environmental chemicals, regulates immune responses in oral squamous cell carcinoma (OSCC)—and that removing it from malignant cells can effectively prevent the formation of tumors.
Published in the journal Proceedings of the National Academy of Science, the study findings provide new insight into the biology of cancer immunosuppression, and identify a new target for cancer immunoprevention or immunotherapy.
Immune checkpoint inhibitors (immunotherapy drugs) are some of the most important treatments that have emerged for treating many cancers, including OSCC. Targeting immune checkpoint molecules such as PD-1, PD-L1 and CTLA4 has demonstrated that immunosuppression plays a significant role in OSCC pathology. But immune checkpoint inhibitors are only effective for about 30 percent of cancer patients, so there is a critical need for researchers to identify new immunotherapy targets.
“This study illustrates how studying the basic science of common environmental pollutants’ suppression of the immune system can result in a hugely impactful new approach to cancer prevention and immunotherapy,” says David Sherr, senior author of the study and a professor of environmental health. The study was conducted in his lab, the Sherr Laboratory, located in the Department of Environmental Health at SPH.
Zhongyan Wang, a research scientist at SPH and a coauthor of the study, used gene-editing techniques to delete a single gene that encodes the AhR from highly malignant mouse oral cancer cells.
After these minimally altered cancer cells were transferred to mice, Jessica Kenison-White, first author of the study, measured tumor growth and compared the strength and nature of the immune response to the cancer cells with the ineffective immune response to the unaltered cancer cells, using digital gene-expression technologies and laser-based enumeration of immune cells. Kenison-White was a PhD student at the School of Medicine and a research scientist in the Sherr Lab during the study.
The researchers found that while unaltered tumor cells overwhelmed the mice within 60 days, removing the AhR gene resulted in zero tumor growth.
“We were surprised but very excited to find such a striking effect, where AhR deletion from the tumor cells completely suppressed tumor growth after seven days in 100 percent of immunocompetent mice, even during extremely long term experiments,” says Kenison-White.
“This suggested to us that AhR plays a critical role in tumor-driven immunosuppression in OSCC, and potentially other cancers as well.”
In addition to this lack of growth the researchers observed a strong tumor-specific immune response marked by a decrease in multiple immune checkpoint markers.
The researchers also discovered that the mice transplanted with AhR-negative oral cancer cells were now 100 percent immune to a challenge with unaltered, highly malignant cancer cells.
“We believe that these findings identified a potential master regulator of multiple immune checkpoints, the suppressive components of the immune system that have been individually targeted in recent years with immunotherapeutics in a way that has revolutionized cancer treatment,” says Sherr.
The results “strongly suggest that targeting this master immune checkpoint regulator with specific inhibitors may ultimately prove as effective, or more effective, at enhancing anti-cancer immune responses than any single therapeutic drug,” Sherr says. “We can see how such a novel drug could be used in a cancer prevention, interception, or treatment modality.”
The study was also coauthored by Kangkang Yang, a research assistant in the Department of Environmental Health at SPH; Megan Snyder, a PhD student at MED and a research scientist in the Sherr Lab; and Francisco J. Quintana, professor of neurology at Brigham and Women’s Hospital and Harvard Medical School.