Lymphocyte-activation gene 3 (LAG3)

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene.

LAG3, is designated CD223 (cluster of differentiation 223).

LAG3 is a cell surface molecule with diverse biologic effects on T cell function. 

It is an immune checkpoint receptor.

The LAG3 gene contains 8 exons. 

It has a close relationship of LAG3 to CD4.

The gene for LAG-3 lies adjacent to the gene for CD4 on human chromosome 12 (12p13) and is approximately 20% identical to the CD4 gene.

The LAG3 protein, belongs to immunoglobulin (Ig) superfamily, comprises a 503-amino acid type I transmembrane protein with four extracellular Ig-like domains, designated D1 to D4.

LAG-3 is expressed on activated T cells,, natural killer cells,[ B cells[12] and plasmacytoid dendritic cells.

LAG3’s main ligand is MHC class II, to which it binds with higher affinity than CD4.

It is a protein that negatively regulates cellular proliferation, activation, and homeostasis of T cells, in a similar fashion to CTLA-4 and PD-1 and has may play a role in Treg suppressive function.

LAG3 helps maintain CD8+ T cells in a tolerogenic state and, working with PD-1, helps maintain CD8 exhaustion during chronic viral infection.

LAG3 is involved in the maturation and activation of dendritic cells.

There are three approaches involving LAG3 that are in clinical development.

A soluble LAG3 which activates dendritic cells.

Antibodies to LAG3 which take the brakes off the anti-cancer immune response: Relatlimab, an anti-LAG3 monoclonal antibody .

LAG-3 may be a better checkpoint inhibitor target than CTLA-4 or PD-1 since antibodies to these two checkpoints only activate effector T cells, and do not inhibit Treg activity, 

An antagonist LAG-3 antibody can both activate T effector cells by downregulating the LAG-3 inhibiting signal, and inhibit induced (i.e. antigen-specific) Treg suppressive activity.

Combination therapies are also ongoing involving LAG-3 antibodies and CTLA-4 or PD-1 antibodies.

There is LAG3 expression on CD8+ tumor-infiltrating lymphocytes.

LAG3 is commonly found on malignant B cells in DLBCL.

LAG3 is found at high levels on CD8 T cells and CD4 Tregs, with almost universal coexpression of PD-1.

Patients who are  PD-L1 high are  fivefold more likely to be LAG3high

Patients who were LAG3high/PD-L1high have an inferior progression-free survival and overall survival compared with patients who were LAG3low/PD-L1high. 

LAG3 expression on T cells and, tumor-associated macrophages (TAMs) are at higher levels than found on CD20+ B cells in the tumor microenvironment. 

LAG3 is frequently expressed on CD4+ Tregs and CD8+ TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL, and tumor-associated macrophages (TAMs.

LAG3high expression is associated with poor outcome independent of conventional prognosticators. 

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