Scientists uncover hidden step in how the immune system prepares to fight cancer

Researchers at Mayo Clinic have uncovered a previously hidden step in how the immune system prepares to fight cancer, a discovery that could help scientists develop more effective and longer-lasting cancer immunotherapies.

Published in Nature Communications, the study found that some cancer-fighting immune cells begin preparing for their role much earlier than previously believed - while they are still maturing in the thymus, an organ behind the breastbone that plays a central role in training T cells, particularly early in life.

The findings challenge the long-standing view that CD8-positive T cells - a type of immune cells that finds and destroys cancer cells - can leave the thymus in an inactive state and acquire their cancer-fighting abilities only after encountering threats elsewhere in the body. Instead, the research suggests that the thymus may help prepare these immune cells for rapid responses before they enter circulation.

CD8-positive T cells are among the immune system's primary cancer-fighting cells. The researchers found that PD-1 - a protein that is the target of several widely used cancer immunotherapy drugs - acts as a brake during their development, helping prevent these cells from becoming exhausted too quickly.

"Cancer immunotherapy has transformed treatment for many patients, but those responses don't always last," says Zhiming Mao, Ph.D., a recent graduate of Mayo Clinic Graduate School of Biomedical Sciences and first author on the paper. "We've discovered that the immune system may begin preparing for its fight against cancer much earlier than we realized. That insight could help us design therapies that are both more powerful and more durable."

PD-1 is already the target of several immune checkpoint inhibitor therapies used to treat a wide range of cancers, making the discovery particularly relevant to ongoing efforts to improve those treatments.

The findings may provide insight into why some immune responses against cancer are powerful but short-lived. Researchers say future therapies may need to strike a balance between boosting the immune system's attack on tumors and preserving the long-term function of cancer-fighting cells.

In preclinical models, removing PD-1 helped these immune cells control certain tumors more effectively. But the stronger response came at a cost: the cells became exhausted sooner, limiting their long-term cancer-fighting ability.

Understanding how these immune cells are programmed at the earliest stages of development gives us a new way to think about improving cancer treatment."

Haidong Dong, M.D., Ph.D., an Iris and Winston Clement Professor of Research at Mayo Clinic and senior author of the study

The findings come as researchers seek ways to make cancer immunotherapies more effective and longer lasting. While these treatments have transformed care for many patients, they do not work for everyone and can lose effectiveness over time.

The findings were based primarily on laboratory and preclinical model studies, and additional research will be needed to determine how they apply to patients.