T cells ditch exhaustion marker to escape tumors and protect against cancer relapse

As the immune system battles cancer, chronic stimulation gradually drives T cells to a state of exhaustion. But some of these exhausted T cells can lose expression of the exhaustion marker LAG3, move out of the tumor and confer long-lasting immunity to cancer in mice, according to a surprising new study published in the Journal of Experimental Medicine that describes a new method to track these cells for the first time.

“The perception was that intratumoral T cells expressing LAG3 perform no function: They either just sit there or they die,” said senior author Dario A.A. Vignali, chair and distinguished professor of immunology at the University of Pittsburgh School of Medicine. “So, it was both surprising and exciting to see that they can actually drive long-lasting immune memory, a finding that has potential translational implications for LAG3-targeting cancer immunotherapies.”

As T cells become progressively more exhausted, they accumulate inhibitory receptors on their surface, including PD1, TIM3 and LAG3. Vignali and his team, including co-first authors Vaishali Aggarwal, Yangxi (Claudia) Sun and Chang Liu, wondered what happened to T cells after they acquired LAG3.

To answer this question, they developed a new mouse model that allowed them to track and map the fate of exhausted T cells. When given the drug tamoxifen, cells expressing LAG3 produce a red fluorescent protein called tdTomato. Only cells expressing LAG3 at the time of drug administration glow red, and the color is permanent, so these cells can be followed—whether or not they continue to express LAG3.

Some exhausted T cells leave

After labeling LAG3-expressing cells in melanoma tumors in mice and tracking them over time, the researchers made two surprising findings: A subset of tdTomato-labeled T cells no longer expressed LAG3, and these so-called single-positive T cells had migrated out of the tumor to the lymph nodes and other tissues.

In contrast, double-positive cells—those expressing tdTomato and LAG3—were found only within the tumor, suggesting that exhausted T cells must lose LAG3 to leave the cancer microenvironment.

Memory depends on departed cells

The researchers next asked what the single-positive cells—those that lost LAG3—were doing outside the tumor and whether they could influence immune memory to tumor cells. To test this, they surgically resected melanoma tumors from mice and then waited one month before rechallenging the animals with the same melanoma cells.

Due to immune memory, the mice could successfully clear the secondary tumor. However, when the single-positive T cells were selectively removed, tumor growth was greatly accelerated, showing that these cells are essential for long-lasting antitumor immunity.

“We identified a specific population of exhausted T cells that can escape the tumor environment and provide lasting immune protection,” said Sun, a graduate student in the Cellular and Molecular Pathology (CMP) Graduate Training Program at Pitt and member of Vignali’s lab. “These departed cells are responsible for long-term memory and preventing tumor recurrence.”

Implications for LAG3 therapies

According to Vignali, many patients with cancer relapse after immunotherapy because they fail to generate a strong, durable memory response.

“The ability to generate a long-lasting memory response that will target the tumor is critically important for effective and durable cancer immunotherapy,” he said. “We are now working to understand whether blocking LAG3 increases exhausted T cell mobility to drive them out of the tumor to seed long-term peripheral immunity.”

These findings could eventually inform new approaches to improve LAG3-targeting immunotherapies.

Who’s behind this story?

Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

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