Lymphocyte-activation gene 3 protein (LAG-3) (LAG-3)

Lymphocyte-activation gene 3 (LAG-3), also known as CD223, is a cell surface inhibitory receptor primarily expressed on activated T cells, natural killer (NK) cells, and B cells [1, 2]. It is a member of the immunoglobulin superfamily and is structurally homologous to CD4, sharing the same primary ligand, Major Histocompatibility Complex class II (MHC II) [1, 4]. The interaction between LAG-3 and MHC II on antigen-presenting cells (APCs) delivers inhibitory signals that suppress T-cell activation, proliferation, and cytokine production, thereby maintaining immune homeostasis and preventing autoimmunity [2, 6]. In the tumor microenvironment, chronic antigen exposure leads to the persistent upregulation of LAG-3, which contributes to T-cell exhaustion and allows tumors to evade immune surveillance [4, 7]. Therapeutic strategies targeting this axis include antagonistic monoclonal antibodies like relatlimab, which block the LAG-3/MHC II interaction to reinvigorate anti-tumor T-cell responses, often in synergy with PD-1/PD-L1 inhibitors [3, 8]. Additionally, soluble LAG-3 fusion proteins such as eftilagimod alpha are utilized as MHC II agonists to activate APCs, enhancing the priming of the adaptive immune response against cancer [5, 9]. References: [1] UniProt (P18627) [2] Andrews LP, et al. (2017) Immunol Rev [3] FDA (2022) Opdualag Approval [4] Maruhashi T, et al. (2020) J Immunother Cancer [5] Immutep (2024) Eftilagimod Alpha [6] Graydon CG, et al. (2021) J Leukoc Biol [7] Ruffo E, et al. (2019) Front Oncol [8] Tawbi HA, et al. (2022) N Engl J Med [9] Brignone C, et al. (2007) Vaccine

Other names

CD223LAG3Lymphocyte-activation gene 3

Antagonism of the LAG-3 inhibitory receptor on T cells to restore immune activity; Agonism of MHC class II on antigen-presenting cells via soluble LAG-3 to promote immune activation.