Seven mysteries of LAG-3: a multi-faceted immune receptor of increasing complexity

Abstract

Despite three decades of research to its name and increasing interest in immunotherapies which target it, LAG-3 remains an elusive co-inhibitory receptor in comparison to the well-established PD-1 and CTLA-4. As such, LAG-3 targeting therapies have yet to achieve the clinical success of therapies targeting other checkpoints. This could, in part, be attributed to the many unanswered questions that remain regarding LAG-3 biology. Of these, we (i) the function of the many LAG-3:ligand interactions; (ii) the hurdles that remain to acquire a high resolution structure of LAG-3; (iii) the under-studied LAG-3 signal transduction mechanism; (iv) the elusive soluble form of LAG-3; (v) the implications of the lack of (significant) phenotype of LAG-3 knockout mice; (vi) the reports of LAG-3 expression on epithelium and (vii) the conflicting reports of LAG-3 expression (and potential contributions to pathology) in the brain. These mysteries which surround LAG-3 highlight how the ever-evolving study of its biology continues to reveal ever-increasing complexity in its role as an immune receptor. Importantly, answering the questions which shroud LAG-3 in mystery will allow maximum therapeutic benefit of LAG-3 targeting immunotherapies in cancer, autoimmunity and beyond.

PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in cancer

“…Immune checkpoint blockade (ICB) fundamentally centers around the relief of effector T cell inhibition with antibodies targeting multiple inhibitory pathways now approved for clinical use ( Burnell et al, 2022 ; Schildberg et al, 2016 ). Prior to the advent of ICB, diseases such as metastatic melanoma were uniformly lethal, whereas today ICB can induce a positive response in nearly half of treated patients ( Larkin et al, 2019 ).…”

Risk factors for eight common cancers revealed from a phenome-wide Mendelian randomisation analysis of 378,142 cases and 485,715 controls

“…Whilst LAG-3 inhibition is an attractive therapeutic target in restoring T-cell function, we demonstrate genetically elevated LAG-3 levels as being associated with reduced CRC, endometrial and lung cancer. In all three of these cancers, the association appears to be at least partly mediated through IL-10 and the seemingly paradoxical relationship between LAG-3 levels and tumourgenesis suggests potentiation of T-cell function by serum LAG-3 rather than cell membrane expressed LAG-3 48 . We identify genetically predicted IL-18 levels as being associated with an increased risk of lung cancer.…”

Risk factors for eight common cancers revealed from a phenome-wide Mendelian randomisation analysis of 378,142 cases and 485,715 controls

“…inhibition is an attractive therapeutic target in restoring T-cell function, we demonstrate genetically elevated LAG-3 levels as being associated with reduced CRC, endometrial and lung cancer. In all three of these cancers, the association appears to be at least partly mediated through IL-10 and the seemingly paradoxical relationship between LAG-3 levels and tumourgenesis suggests potentiation of T-cell function by serum LAG-3 rather than cell membrane expressed LAG-3 48 . We identify genetically predicted IL-18 levels as being associated with an increased risk of lung cancer.…”