Lymphocyte-activation gene 3 (LAG-3) is a protein found on the surface of various immune cells, including T cells, natural killer (NK) cells, and dendritic cells. It acts as an immune checkpoint receptor, playing a role in regulating the body’s defense system. LAG-3’s presence helps maintain a delicate balance within the immune system, preventing it from overreacting while allowing it to respond to threats.
How LAG-3 Controls Immune Responses
LAG-3 functions as an inhibitory co-receptor, meaning it puts “brakes” on the activity of T cells. It is structurally similar to CD4, another molecule on T cells, but binds to its primary ligand, Major Histocompatibility Complex (MHC) class II molecules, with a higher affinity. This binding occurs on antigen-presenting cells (APCs), which are cells that display fragments of pathogens or abnormal proteins to T cells.
When LAG-3 binds to MHC class II, it transmits inhibitory signals into the T cell, reducing its activation, proliferation, and production of immune signaling molecules called cytokines. This dampening effect helps to prevent excessive immune responses that could harm healthy tissues, contributing to immune tolerance. Beyond MHC class II, LAG-3 also interacts with other ligands, such as fibrinogen-like protein 1 (FGL1), galectin-3, and liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin), further influencing T cell function.
LAG-3’s Link to Illness
Dysregulation of LAG-3’s inhibitory function is implicated in several diseases, particularly cancer. In tumors, cancer cells can exploit LAG-3 to evade destruction by the immune system. This occurs as tumors create an immunosuppressive environment that promotes the upregulation of LAG-3 on tumor-infiltrating lymphocytes (TILs), leading to T cell exhaustion and dysfunction.
LAG-3 is frequently co-expressed with other inhibitory immune checkpoint molecules, like PD-1, on T cells within the tumor microenvironment. This co-expression can lead to a synergistic suppression of anti-tumor immunity. Beyond cancer, LAG-3 has also been linked to autoimmune diseases, where the immune system mistakenly attacks the body’s own healthy tissues. In these conditions, strengthening the LAG-3 pathway could potentially help restore immune tolerance and prevent autoimmune attacks.
Developing LAG-3 Targeted Treatments
Understanding LAG-3’s role in immune regulation has opened avenues for developing new therapies, especially in cancer immunotherapy. The primary strategy involves “LAG-3 inhibitors,” which are designed to block LAG-3’s inhibitory activity, thereby “releasing the brakes” on the immune system to allow it to more effectively fight cancer. These inhibitors, often monoclonal antibodies, aim to reinvigorate exhausted T cells and enhance anti-tumor responses.
A significant advancement in this area is the FDA approval in March 2022 of relatlimab, the first LAG-3 blocking antibody, in combination with nivolumab, an anti-PD-1 therapy. This combination, marketed as Opdualag, is approved for treating certain types of advanced melanoma. Clinical trials, such as RELATIVITY-047, demonstrated that this dual checkpoint blockade significantly improved progression-free survival compared to nivolumab alone, more than doubling the median time patients lived without their disease worsening. Research continues with numerous LAG-3-targeting molecules in various stages of clinical development, including bispecific antibodies that target multiple checkpoints simultaneously. While the focus is largely on cancer, researchers are also exploring LAG-3 modulation for autoimmune diseases, potentially by using approaches that enhance LAG-3’s inhibitory signals to re-establish immune tolerance.