Adding detection of the SYNGR3 protein on immune cells to current protocols that look for presence of the p16 tumor suppressor protein could lead to a more reliable way of determining which patients with low-risk head and neck cancer need less intensive treatment. The study, led by UNC Lineberger Comprehensive Cancer Center researchers and colleagues, was published in Cancer Research Communications.
The researchers said their findings were unexpected as SYNGR3 is typically found in the brain and not in immune cells.
About 30% of newly diagnosed squamous cell head and neck cancers in the U.S. are caused by infection with the human papilloma virus (HPV) and the number of such cancers is increasing. Since HPV-positive head and neck cancer patients have significantly better outcomes compared to HPV-negative cases, it is crucial to correctly diagnose these patients before considering de-intensified treatment plans.
However, a subset of HPV-positive patients has low survival chances, so researchers have been interested in identifying ways to better diagnose HPV-positive disease and also find a way to stratify HPV-positive patients to guide treatment decisions that could help many avoid unnecessary therapies.
“Although many patients with HPV-positive head and neck cancers have higher cure rates compared to their HPV-negative counterparts, standard treatments can sometimes result in harsh side-effects,” said Antonio L. Amelio, PhD, who was an associate professor of cancer cell biology at UNC Lineberger when the research was conducted and is the corresponding author of the article. “Clinical trials have previously revealed that when some HPV-positive head and neck cancer patients are given lower-dose chemotherapy, they have fewer side-effects and an increased quality of life compared to those receiving higher doses.” Amelio cautioned that before treatment intensity can be lessened, stratifying HPV-positive diagnoses is crucial.
The researchers initially looked at 11 tissue samples from patients at UNC to validate their theory, and then analyzed over 100 historical cases from the Carolina Head and Neck Cancer (CHANCE) study to increase reliability. The investigators were able to determine that patients with high levels of the immune protein SYNGR3 had significantly better prognoses, with 60% of these patients living five years or more after diagnosis. When looking at combined factors of high p16 and high SYNGR3 expression, the investigators determined that patients with both factors had over an eight times lower chance of their disease worsening.
“While most other studies have focused on cancer cells, a hugely innovative advance of this study is identification of markers in the tumor-infiltrating immune cells that has the potential to improve our classification of HPV-positive and HPV-negative cancers,” said Wendell G. Yarbrough, MD, MMHC, FACS, Thomas J. Dark distinguished professor of otolaryngology/head and neck surgery at UNC Lineberger and author on the paper. “Tests for SYNGR3 that are additive to testing of p16 in tumor cells will help clinicians know which tumors are truly HPV-associated. This is particularly important as new and de-escalated therapies for HPV-positive head and neck cancers become common for treatment.”
“What’s really puzzling is that SYNGR3 is normally expressed in the brain and not in immune cells, suggesting that some unexpected biology is established between HPV-positive tumor cells and immune cells,” Amelio noted. The scientists said the next steps of their research will include developing a better understanding of the regulatory and functional role of SYNGR3-positive immune cells, with the ultimate goal of designing novel immunotherapies for HPV-positive head and neck cancer patients.
Authors and disclosures
In addition to Amelio and Yarbrough, the other authors at UNC include Jason Tasoulas, MD, DMD, Ryan M. Murphy, PhD, Alessandro Porrello, PhD, Miranda B. Carper, PhD, Yi-Hsuan Tsai, PhD, Alisha R. Coffey, PhD, Sunil Kumar, PhD, Travis P. Schrank, MD, PhD, Bentley R. Midkiff, Stephanie Cohen, PhD, Ashley H. Salazar, Michele C. Hayward, D. Neil Hayes, MD, Andrew Olshan, PhD, Gaorav P. Gupta, MD, PhD, and Chad V. Pecot, MD. Peter YF. Zeng and Anthony C. Nichols, MD, are at University of Western Ontario, London, Ontario, Canada.
The research was supported by NIH grants T32GM119999, F31DE028749, T90DE021986 and T32CA211056; a CIHR Vanier Canada Graduate Scholarship and a PSI Foundation Fellowship; a Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers Fund; a University Cancer Research Fund award; and, in part, by a NIH Developmental Research Program Grant from the Yale Head and Neck SPORE (P50-DE030707) and an NIH grant (R01DE030123). Pecot was also supported in part by NIH grants R01CA215075, R01CA258451 and 1R41CA246848, the Lung Cancer Research Foundation, the Free to Breathe Metastasis Research Award and a North Carolina Biotechnology Translation Research Grant. The Office of Genomics Research, Lineberger Bioinformatics Core, and UNC Pathology Services Core are supported in part by the NCI Center Core Support Grant (5P30CA016080-42) to UNC Lineberger.
Pecot and Amelio have filed a patent on the use of SYNGR3 as a cancer biomarker. Amelio is a Global Advisory Board member and paid consultant for the LG Chem Life Sciences Innovation Center. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.