Exhausted T cells shed LAG3 marker to leave tumors and sustain long-term immunity in mice

Researchers at the University of Pittsburgh have discovered that some exhausted T cells inside tumors can shed the exhaustion marker LAG3, exit the tumor microenvironment, and establish long-lasting immune memory that protects against cancer relapse in mice. The findings, published in the Journal of Experimental Medicine, challenge the prevailing view that LAG3-expressing T cells are terminally dysfunctional and confined to the tumor.

To track the fate of LAG3-expressing cells, the team developed a mouse model in which administration of tamoxifen induces permanent red fluorescent labeling of any cell expressing LAG3 at that moment. This allowed the researchers to follow labeled cells over time regardless of whether they continued to express the marker.

After labeling LAG3-positive T cells in melanoma tumors, the researchers observed two distinct populations. Double-positive cells retaining both the fluorescent label and LAG3 expression remained trapped inside the tumor. In contrast, a subset of single-positive cells kept the fluorescent label but lost LAG3 expression and migrated to lymph nodes and other tissues.

To test the functional importance of these departed cells, the researchers surgically removed primary melanoma tumors and rechallenged the mice with the same cancer cells one month later. Mice with intact single-positive T cells cleared the secondary tumors, but selective depletion of these cells led to greatly accelerated tumor growth, demonstrating their essential role in long-term antitumor immunity.

Senior author Dario Vignali, chair of immunology at the University of Pittsburgh School of Medicine, noted that many cancer patients relapse after immunotherapy because they fail to generate durable memory responses. The study suggests that LAG3 loss may be a prerequisite for exhausted T cells to escape the tumor and seed peripheral immune memory.

The researchers are now investigating whether therapeutic blockade of LAG3 could enhance the mobility of exhausted T cells, driving them out of tumors to establish lasting systemic immunity. If confirmed, the findings could inform strategies to improve the durability of LAG3-targeting cancer immunotherapies.

The work was led by co-first authors Vaishali Aggarwal, Yangxi (Claudia) Sun, and Chang Liu, and supported by the University of Pittsburgh. The study appears in the Journal of Experimental Medicine (DOI: 10.1084/jem.20241968).