The human body is an intricate network of systems, with genes serving as fundamental blueprints that guide its development and function. These genes contain instructions for building proteins, which are the workhorses of our cells, performing a vast array of tasks to maintain health. Among the many genes that orchestrate our biological processes, the Lymphocyte-activation gene 3, or LAG3, holds particular significance. Understanding genes like LAG3 helps illuminate how our immune system operates and provides insights into conditions that impact human well-being.
The LAG3 Gene and Its Product
The LAG3 gene, formally known as Lymphocyte-activation gene 3, is located on chromosome 12 in humans, specifically at band 12p13.31. This gene provides instructions for the creation of the LAG3 protein, which belongs to the immunoglobulin superfamily. The LAG3 protein is primarily found on the surface of various immune cells, including activated T cells, natural killer cells, and plasmacytoid dendritic cells.
The LAG3 protein functions as a transmembrane receptor, meaning it spans the cell membrane, with parts extending both outside and inside the cell. Its extracellular portion, which consists of four immunoglobulin-like domains, interacts with other molecules outside the cell. This allows LAG3 to bind to specific partners, influencing the activity of the immune cells on which it resides.
LAG3’s Role in Immune Regulation
The LAG3 protein regulates the immune system by acting as an “immune checkpoint” molecule. It helps prevent excessive or harmful immune responses, maintaining a balanced state within the body. LAG3 achieves this by interacting with other molecules, primarily Major Histocompatibility Complex (MHC) class II molecules, found on antigen-presenting cells.
When LAG3 binds to MHC class II, it delivers an inhibitory signal that dampens the activity of T cells. This interaction can reduce T-cell proliferation, activation, and the production of pro-inflammatory signaling molecules. The inhibitory function of LAG3 contributes to immune tolerance, preventing the immune system from mistakenly attacking the body’s own healthy tissues.
LAG3 in Disease Development
When the normal regulatory function of LAG3 is disrupted, it can contribute to the development and progression of various diseases. In cancer, LAG3 often becomes highly expressed on tumor-infiltrating T cells. This increased expression contributes to immune suppression within the tumor microenvironment, allowing cancer cells to evade detection and destruction by the immune system. For example, LAG3 expression on CD8+ T cells in tumors like non-small cell lung cancer and melanoma correlates with a more exhausted T-cell state and can be associated with poorer patient outcomes.
Beyond cancer, dysregulation of LAG3 is also implicated in autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues. In these conditions, an impaired or altered regulatory function of LAG3 might lead to an overactive immune response. Alterations in LAG3+ regulatory T cells have been observed in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, suggesting a potential role in disease pathology.
Therapeutic Strategies Targeting LAG3
Understanding LAG3’s role in disease has spurred the development of new therapeutic interventions, particularly in cancer immunotherapy. Strategies often involve LAG3-blocking antibodies designed to “release the brakes” on the immune system. These antibodies aim to block the inhibitory signals transmitted by LAG3, reactivating T cells to mount a stronger anti-tumor response.
Relatlimab is an example of a LAG3-blocking antibody used in clinical applications. It works by binding to LAG3 and preventing its interaction with ligands like MHC class II and fibrinogen-like protein-1, which effectively reverses LAG3-mediated inhibition of T-cell function. The U.S. FDA approved a fixed-dose combination of relatlimab and nivolumab, a PD-1 blocker, for treating unresectable or metastatic melanoma. This combination leverages the distinct mechanisms of action of both LAG3 and PD-1 inhibition, leading to enhanced anti-tumor activity compared to nivolumab alone, as observed in trials like RELATIVITY-047. While the primary focus remains on cancer, research continues to explore the potential of targeting LAG3 for autoimmune conditions, aiming to suppress overactive immune responses.