LAG-3—An incompletely understood target in cancer therapy

LAG-3 is a member of the immunoglobulin superfamily expressed on activated T cells, but also on other immune cells. It has significant homology to CD4. Both molecules have four extracellular Ig-like domains with similar structural motifs but the sequence identity between LAG-3 and CD4 is low. Furthermore, unlike CD4 LAG-3 restrains T cell responses and antibodies targeting this receptor are emerging drugs in cancer immunotherapy. A combination of LAG-3 and PD-1 antibodies has already been approved for the treatment of metastatic melanoma. Despite this success, its biology is still not well understood. Here we summarize the current knowledge on expression, ligands, and function of LAG-3. We point to the differences between LAG-3 and other inhibitory immune checkpoints and describe obstacles to study the role of this receptor in T cell activation processes. Finally, we discuss future directions for scientific efforts to come to a more complete understanding of the biology of this eminent immune checkpoint.