The immune checkpoint receptor LAG3: Structure, function, and target for cancer immunotherapy

Lymphocyte activation gene 3 protein (LAG3) is an immune checkpoint receptor that is highly upregulated on exhausted T cells in the tumor microenvironment. LAG3 transmits inhibitory signals to T cells upon binding to MHC class II and other ligands, rendering T cells dysfunctional. Consequently, LAG3 is a major target for cancer immunotherapy with many anti-LAG3 monoclonal antibodies (mAbs) that block LAG3 inhibitory activity in clinical trials. In this review, we examine the molecular basis for LAG3 function in light of recently determined crystal and cryoEM structures of this inhibitory receptor. We review what is known about LAG3 interactions with MHC class II, its canonical ligand, and the newly discovered ligands FGL1 and the T cell receptor (TCR)-CD3 complex, including current controversies over the relative importance of these ligands. We then address the development and mechanisms of action of anti-LAG3 mAbs in clinical trials for cancer immunotherapy. We discuss new strategies to therapeutically target LAG3 using mAbs that not only block the LAG3-MHC class II interaction, but also LAG3 interactions with FGL1 or TCR-CD3, or that disrupt LAG3 dimerization. Finally, we assess the possibility of developing mAbs that enhance, rather than block, LAG3 inhibitory activity as treatments for autoimmune diseases.