Lymphocyte-Activation Gene 3 (LAG-3) is a protein found on the surface of immune cells, particularly T cells. It functions as an immune checkpoint receptor, regulating the body’s immune responses. LAG-3 helps maintain a balanced immune system, preventing overactivity. Understanding this protein is important for developing therapies that modulate immune responses.
Understanding LAG-3 and Its Mechanism
LAG-3 is an immune checkpoint protein that controls immune cell activity. It is predominantly found on the surface of T cells, including activated CD4+ and CD8+ T cells, as well as regulatory T cells (Tregs).
Structurally, LAG-3 is a type I transmembrane protein with four extracellular immunoglobulin-like domains. It also possesses a unique extra loop in its membrane-distal domain, which distinguishes it from similar proteins like CD4.
LAG-3 primarily binds to Major Histocompatibility Complex (MHC) class II molecules with higher affinity than CD4, influencing T cell receptor (TCR) signaling. When LAG-3 engages with MHC class II on antigen-presenting cells (APCs), it transmits inhibitory signals that reduce T cell activation and proliferation. This interaction can lead to decreased production of pro-inflammatory cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). LAG-3 also binds to other ligands like fibrinogen-like protein 1 (FGL1) and galectin-3, further contributing to its suppressive effects on T cells.
LAG-3’s Role in Immune Balance
LAG-3 helps maintain immune homeostasis, acting as a natural “brake” on the immune system. This prevents excessive immune responses that could damage healthy tissues, ensuring the immune system responds appropriately without widespread inflammation.
The protein is also involved in promoting self-tolerance, which is the immune system’s ability to recognize and not attack the body’s own cells and tissues. LAG-3 contributes to this by regulating the activity of T cells that might otherwise target self-antigens, thus helping to prevent autoimmune reactions.
LAG-3 contributes to T cell exhaustion, a state of T cell dysfunction that can occur during chronic infections. In such prolonged antigen exposure, LAG-3 expression helps to dampen T cell activity, potentially limiting tissue damage from sustained inflammation.
LAG-3 as a Target in Cancer Immunotherapy
Cancer cells can exploit immune checkpoint pathways, including LAG-3, to evade detection and destruction by the immune system. In the tumor microenvironment, LAG-3 is often highly expressed on exhausted T cells, which have lost their effective anti-tumor function due to persistent stimulation. This elevated LAG-3 expression contributes to the immunosuppressive environment around tumors, allowing cancer cells to proliferate unchecked.
Targeting LAG-3 with immune checkpoint blockade therapies aims to “release the brakes” on anti-tumor T cells. Monoclonal antibodies like relatlimab prevent LAG-3 from binding to its ligands, restoring T cells’ ability to recognize and attack cancer cells. Relatlimab, a human IgG4 antibody, specifically blocks LAG-3 expressed on T cells, inhibiting its suppressive effects.
LAG-3 inhibitors are being investigated in clinical trials, often in combination with other immune checkpoint inhibitors like those targeting PD-1 (Programmed Cell Death Protein 1). The rationale behind these combination therapies is that LAG-3 and PD-1 contribute to T cell exhaustion through different, yet synergistic, mechanisms. For instance, PD-1 primarily interferes with T cell receptor (TCR) signaling, while LAG-3 directly affects TCR engagement with MHC class II molecules.
A notable example of this approach is the combination of relatlimab with nivolumab (an anti-PD-1 antibody), which received FDA approval in March 2022 for the treatment of unresectable or metastatic melanoma. In the Phase II/III RELATIVITY-047 trial, this combination significantly improved progression-free survival in patients with previously untreated metastatic or unresectable melanoma, with a median progression-free survival of 10.1 months compared to 4.6 months with nivolumab alone. The combination therapy generally demonstrated a manageable safety profile, with side effects comparable to or only modestly higher than nivolumab monotherapy. This dual blockade aims to provide a more robust and sustained anti-tumor T cell response, potentially overcoming resistance to single-agent PD-1 blockade in some patients.
Broader Therapeutic Horizons for LAG-3
Beyond cancer, LAG-3 holds potential for therapeutic applications in other diseases where immune modulation is beneficial. In autoimmune diseases, where the immune system is overactive and mistakenly attacks healthy tissues, activating LAG-3 could help suppress these unwanted immune responses.
Research is exploring LAG-3 agonists, which are molecules that enhance LAG-3’s inhibitory function, to calm an overactive immune system. For example, studies in animal models of autoimmune diseases like type 1 diabetes and hepatitis have shown that enhancing LAG-3 activity can reduce T cell-mediated inflammatory damage.
Similarly, in chronic infectious diseases, where T cell exhaustion can hinder effective pathogen clearance, blocking LAG-3 might enhance the immune response. By releasing the inhibitory effects of LAG-3, T cells could regain their full function, potentially leading to better control or elimination of persistent infections.