New research published this week in Cell provides novel insights into the mechanisms of LAG3, an immune checkpoint that inhibits T cell activity and stymies their tumor-killing activity.
Despite the U.S. Food and Drug Administration’s recent approval of the cancer immunotherapy drug relatlimab, a LAG3-blocking antibody, little is known about how LAG3 works. To learn more, Dario Vignali, Ph.D., distinguished professor and chair of the Department of Immunology and member of UPMC Hillman Cancer Center collaborated with Haopeng Wang, Ph.D., a former graduate student of Vignali’s and now associate professor, at ShanghaiTech University, and researchers from other institutions in China.
The team found that after a ligand binds to LAG3, an enzyme called E3 ubiquitin ligase CBL modifies the cytoplasmic domain of LAG3 by adding a ubiquitin molecule, which in turn exposes another part of LAG3 necessary for inhibitory signaling.
“Just as most pumps need to be primed with fluid before they can work, this study suggests that the ubiquitination of LAG3 by CBL primes LAG3 so it can carry out inhibitory signaling,” said Vignali.
When Jian Cui in the Vignali lab and the team looked at samples from melanoma patients, they found that high CBL expression correlated with enhanced T cell exhaustion, impaired antitumor immunity and poorer survival outcomes. However, the same patients also responded better to relatlimab, suggesting that CBL could act as a novel biomarker for LAG3 blockade response.