Yale researchers have made an unexpected discovery—turncoat T cells that help a tumour evade other cancer-fighting immune T cells—in a study of patients living with advanced melanoma.

The study by Yale Cancer Center (YCC) researchers at Yale School of Medicine (YSM) discovered that not all CD8⁺ T cells are allies in a body's fight against cancer cells. Patients living with severe melanoma who had increased levels of suppressor, regulatory CD8⁺ T cells had worse survival outcomes.

The study is published in the journal Nature Immunology.

"In some patients with melanoma, these CD8⁺ regulatory T cells are fighting against our own immune response and attack other T cells fighting the tumours —it's an alternative function, besides killing the cancer cells," said first author, Dr Benjamin Lu, MD, PhD, a YCC medical oncologist in YSM's Department of Neurology.

He says these unexpected results are clinically important to help better understand how to treat these patients living with melanoma and potentially other cancers.

"Our goal was to learn how well the immune system could respond to melanoma cancers," said Lu. "Taking blood samples from patients, we used high-resolution single-cell techniques to understand the relationship between CD8⁺ T cells and their evolution in the blood and tumor. We wanted to understand how that could be clinically useful for predicting patient outcomes and how they'll respond to immunotherapies."

Senior author Dr. David A. Hafler, professor of neurology and immunobiology and chair of the Department of Neurology at Yale School of Medicine, noted that these CD8⁺ T cells, identified by the expression of inhibitory KIR proteins, were recently found to have regulatory-like function in the context of autoimmune diseases, such as multiple sclerosis, and infection.

"These novel investigations extend the role of these newly discovered suppressor cells and their association with worse overall survival of patients with cancer provides a potential new immunotherapeutic approach by targeting these cells," Hafler said.

The factors that affect a patient's CD8⁺ T cell levels

Lu said our immune system has the ability to increase or decrease the number of CD8⁺ cells and there are several factors affecting why certain patients may have more of them.

"We actually find this CD8⁺ T cell subpopulation in everyone— it's just a matter of what proportion we see in the blood," Lu said. "We know that as we get older, the number of CD8⁺ regulatory T cells tends to go up. They also tend to go up when there's an active infection or inflammation."

By better understanding the role of CD8⁺ regulatory T cells, the researchers hope the findings will improve the effectiveness of immunotherapies, improving survival rates for patients living with advanced melanoma. Researchers also emphasised the importance of testing for CD8⁺ regulatory T cells in the patient's blood to help determine who might benefit from current and future cancer therapies.