LAG3's Enigmatic Mechanism of Action

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.

Keywords: LAG3; Lymphocyte activation gene-3; checkpoint inhibition; immune checkpoint; immune checkpoint inhibitors; immune exhaustion; mechanism of action.

Figure 1

LAG3 transcription is upregulated following activation through the T cell Receptor (TCR) or from certain cytokines. Once translated, LAG3 resides in late endosomes for subsequent trafficking to the cell surface.There, LAG3 exists as an oligomer or monomer. While seemingly necessary for MHCII binding, LAG3 oligomerization may or may not be required for interaction with other LAG3 ligands (α-syn, Gal-3, L-SECtin or FGL-1). Upon ligand binding, LAG3 inhibits early steps of the TCR pathway in a manner dependent on LAG3’s cytoplasmic domain. This prevents activation of transcription factors, including NFAT, thereby decreasing cytokine production and proliferation. LAG3 surface expression is regulated by metalloproteases ADAM10/17 that proteolytically cleave LAG3, releasing it in soluble form (sLAG-3). LAG3 surface expression may also be regulated by endocytosis, which can be accelerated by ligand binding.