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…
In a surprising study, researchers have discovered that certain exhausted T cells can shed their exhaustion marker LAG3 and escape from tumors, conferring long-lasting immunity against cancer in mice. This finding, published in the Journal of Experimental Medicine, could lead to improved cancer immunotherapies.
Traditionally, it was believed that intratumoral T cells expressing LAG3 were either inactive or dying. However, the study's senior author, Dario A.A. Vignali, revealed that these exhausted T cells can in fact drive long-lasting immune memory, which has potential translational implications for LAG3-targeting cancer treatments.
To investigate this phenomenon, the researchers developed a new mouse model that allowed them to track the fate of exhausted T cells. When administered the drug tamoxifen, cells expressing LAG3 produced a red fluorescent protein called tdTomato. This enabled the team to follow these cells over time, regardless of whether they continued to express LAG3.
The researchers made two key discoveries. Firstly, a subset of tdTomato-labeled T cells lost LAG3 expression and migrated out of the tumor to the lymph nodes and other tissues. These single-positive T cells were found outside the tumor, suggesting that exhausted T cells must lose LAG3 to leave the cancer microenvironment. Secondly, double-positive cells—those expressing both tdTomato and LAG3—remained within the tumor, indicating that exhausted T cells must lose LAG3 to migrate.
The team then tested the functional significance of these single-positive T cells. By surgically removing melanoma tumors from mice and then rechallenging the animals with the same melanoma cells a month later, they observed that mice without the single-positive T cells experienced accelerated tumor growth. This finding demonstrates that these cells are essential for long-lasting antitumor immunity.
Vaishali Aggarwal, a co-first author and graduate student, emphasized the importance of these cells in generating immune memory and preventing tumor recurrence. Vignali added that many cancer patients relapse after immunotherapy because their bodies fail to generate a strong, durable memory response. The ability to generate such a memory response is crucial for effective and durable cancer immunotherapy.
The researchers are now exploring whether blocking LAG3 can increase exhausted T cell mobility, driving them out of the tumor and promoting long-term peripheral immunity. These findings could potentially inform new approaches to improve LAG3-targeting immunotherapies.
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