Abstract
LAG3 is an important immune checkpoint with relevance in cancer, infectious disease and autoimmunity. However, despite LAG3’s role in immune exhaustion and the great potential of LAG3 inhibition as treatment, much remains unknown about its biology, particularly its mechanism of action. This review describes the knowns, unknowns and controversies surrounding LAG3. This includes examination of how LAG3 is regulated transcriptionally and post-translationally by endocytosis and proteolytic cleavage. We also discuss the interactions of LAG3 with its ligands and the purpose thereof. Finally, we review LAG3’s mechanism of action, including the roles of LAG3 intracellular motifs and the lack of a role for CD4 competition. Overall, understanding the biology of LAG3 can provide greater insight on LAG3 function, which may broaden the appreciation for LAG3’s role in disease and potentially aid in the development of targeted therapies.
Highlights
Immune cells are chronically activated during cancer, chronic infection, autoimmune disease and graft versus host disease
lymphocyte activation gene3 (LAG3) is mostly studied on conventional T cells and T regulatory cells, but is expressed on unconventional T cells (i.e., gdT cells, mucosal-associated invariant T (MAIT) cells, invariant natural killer T cells), NK cells, B cells, plasmacytoid dendritic cells and neurons [5, 9,10,11]
Immune checkpoint blockade is revolutionizing the treatment of immunogenic cancers
Summary
Immune cells are chronically activated during cancer, chronic infection, autoimmune disease and graft versus host disease. In response to this persistent activation, immune cells become exhausted, losing the ability to produce cytokines or proliferate. Inhibiting ICs can bolster the immune response against tumors and greatly improve survival in cancer patients [1] This translational potential has prompted a flurry of research into IC inhibition as treatment, such that our knowledge of IC biology and mechanism of action lags. This is especially true for the IC–lymphocyte activation gene (LAG3). We review mechanisms of LAG3 expression, ligand binding and function and identify major gaps in knowledge
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