Unexpected findings in study of T cells considered front-line fighters against advanced melanoma

Yale researchers made an unexpected discovery—turncoat T cells that help a tumor evade other cancer-fighting immune T cells—in a study of patients living with advanced melanoma that was published Nov. 28 in Nature Immunology.

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. In a new study, patients living with severe melanoma who had increased levels of suppressor, regulatory CD8⁺ T cells had worse survival outcomes. The study’s results were published in Nature Immunology on November 28.

CD8+ regulatory T cells show alternative function, attacking other T cells fighting melanoma

“In some patients with melanoma, these CD8⁺ regulatory T cells are fighting against our own immune response and attack other T cells fighting the tumors —it’s an alternative function, besides killing the cancer cells,” said first author, Dr. Benjamin Lu, 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.”

Melanoma research advances the understanding of these suppresser T cells, identified in autoimmune diseases

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,” Dr. Hafler said.

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

Dr. Lu said our immune system has the ability to increase or decrease the number of CD8+ cells and there are several factors effecting 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 tend to go up. They also tend to go up when there's an active infection or inflammation.”

Implications on future cancer research and immunotherapies

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 emphasized 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.

Other Yale authors included Liliana Lucca, Wesley Lewis, Jiping Wang, Pierre-Paul Axisa, Sarah Reeves, Nicholas Buitrago-Pocasangre, Giang Pham, Mina Kojima, Wei Wei, Lilach Aizenbud, Antonetta Bacchiocchi, Lin Zhang, Joseph Walewski, Veronica Chiang, Kelly Olino, James Clune, Ruth Halaban, Yuval Kluger, and Harriet Kluger . Researchers from MIT’s Broad Institute at Harvard University and Repertoire Immune Medicines in Switzerland and Cambridge, Mass. also contributed to this study.

This research was supported by the National Institutes of Health grant T32 CA233414 (to BYL), K12 CA215510 (to BYL), T15 LM007056-36 (to WL), R01 CA121974 (to HMK), R01 CA269286 (to HMK), R01 CA227473 (to HMK and DAH), U24 AI11867 (to DAH), R01 AI22220 (to DAH), 5 UM 1HG009390 (to DAH), and P01 AI039671 (to DAH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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