New Study Pinpoints Immunotherapy Targets for Head and Neck Cancer

Head and neck squamous cell carcinoma, an aggressive cancer diagnosed in more than 70,000 patients each year, is often treated with surgery and radiation. While prognosis for some cases has improved, these treatments often lead to a considerable decline in quality of life for patients.

Immunotherapy – using a patient’s own immune system to fight cancer – has emerged in recent years as a new alternative treatment. But getting the immune system to find and attack certain tumors has been difficult.

New tumor targets discovered through research at the Medical College of Wisconsin (MCW) could change that.

Joseph Zenga, MD, Donald S. Blatnik, MD and Sharyn B. Blatnik Professor of Head and Neck Surgical Oncology and Reconstruction (pictured right), and his team have identified proteins in head and neck squamous cell carcinoma tumors that could be potential targets for re-engineered immune cells to find and attack.

Published in the journal JAMA Otolaryngology-Head & Neck Surgery, the research could lead to both better treatments and quality of life for patients.

“We showed conclusively that these proteins exist in head and neck cancer, and now we can move forward with developing an immunotherapy that can harness the body’s own immune system to eliminate this aggressive cancer,” Dr. Zenga says.

Searching for Cancer-testis Antigens for Precision-Targeted Immunotherapy

In his lab, surgeon scientist Dr. Zenga focuses on finding innovative targets for immunotherapy to better treat head and neck cancer patients. His work drew the attention of Abdullah A. Memon (pictured right), a third-year MCW medical student whose mother has head and neck cancer.

“I’ve seen firsthand how these cancer patients endure morbid surgeries and radiation, often with life-altering impacts on their ability to communicate, smile, and live comfortably,” says Memon, first author on the paper. “When you lose those basic human expressions, your quality of life is deeply affected.”

To find targets in head and neck cancer for the immune system to attack, the team used a wide variety of technologies to search for cancer-testis antigens (CTAs). These proteins are only expressed in tumors and in certain reproductive organs, like testes. That makes them an attractive target for immunotherapy, since reproductive organs are immune-privileged – meaning they are protected from immune system responses.

To find which CTAs could be leveraged for therapy in head and neck tumors, the researchers used tissue from 33 biopsied tumors and ran them through genetic sequencing tools, including bulk RNA sequencing and single-cell RNA sequencing. These tools reveal which CTAs are most commonly present in tumors.

Of the 67 CTAs they found to be to be specific to head and neck tumors, 14 were validated across a cohort of more than 600 tumors, representing the most promising precision targets for immunotherapy.

They validated their findings against existing tumor databases and also showed that the proteins are absent from benign tissues of the body. This strengthens the case that the proteins could be safe and specific targets for new head and neck cancer therapies.

The researchers also found that no two tumors were exactly alike, each showed its own pattern of CTA expression. That finding points to the need for personalized cancer treatments tailored to each patient’s tumor profile.

“There’s a lot of variability in which CTAs a tumor expresses and the degree to which they express them,” Memon says. “That heterogeneity gives us the opportunity to exploit their expression and design personalized precision therapies.”

Next Step: Engineering T Cells

That precision therapy is called T Cell Receptor (TCR)-engineered therapy, which was first approved by the FDA in 2024 for a rare cancer called synovial cell sarcoma. The target of this therapy was a CTA the researchers have also found to be expressed in head and neck tumors.

The eventual goal of this therapy is to identify CTAs in a patient’s tumor, collect the patient’s T cells, and re-engineer them with special receptors that recognize those CTAs. The enhanced T cells are then multiplied in the lab and infused back into the patient, where they seek out and destroy the tumor.

Memon plans to take a year off medical school to continue this research, next working to isolate specific T cell receptors that could be used to target CTAs.

“Developing effective therapies like this isn’t just work for Dr. Zenga, it’s a life’s mission,” Memon says. “He truly invests in research and in trainees like me, and has really motivated me to continue this work into targeted therapies for suffering patients.”