fig1

Figure 1. (A) MHCII is one of the main ligands of LAG-3 and the inhibition of LAG-3 in tumor cells is a potential therapeutic option for patients resistant to PD-L1 immunotherapy. The LAG-3 protein structure consists of an extracellular, a transmembrane, and a cytoplasmic part. The extracellular part is composed of four IgG domains: D1, which contains a loop domain rich in proline and an in-chain species-specific disulfide bond, and D2-D4. In the transmembrane part, the metalloproteinases ADAM10/17 regulate LAG-3’s breakaway from the cell membrane. The cytoplasmic part consists of the serine phosphorylation site, the KIEELE motif, and the EP repeat motif. (B) The principal ligand of LAG-3 is MHCII, to which it binds with greater affinity than CD4. LAG-3 is involved in DC maturation and activation; it is involved in decreased T cell proliferation and cytokine production, upregulating the production of interleukins and NF-κB, via PI3K/Akt signaling. LAG-LSEC interaction is positively correlated with tumor growth, while LAG-3-Ig fusion proteins inhibit CD4/MHCII-dependent cellular adhesion assays, modulating MHCII-TCR signaling. (C) Cells with increased LAG-3 expression, as well as basic regulators of LAG-3 expression and interleukins regulated by LAG-3. LAG-3 is highly expressed in various types of immune cells (CD8+, Tregs, B cells, and NK cells), and is positively (IL-1, IL-2) or negatively (IL-4) regulated by interleukins. Additionally, it acts as a regulator of IL-10. ADAM: a disintegrin and metalloproteinase; APC: antigen-presenting cell; CD3: cluster of differentiation 3; CD4: cluster of differentiation 4; CD8: cluster of differentiation 8; IL-1: interleukin 1; IL-2: interleukin 2; IL-4: interleukin 4; IL-10: interleukin 10; LSECs: liver sinusoidal endothelial cells; MHCII: major complex histocompatibility complex class II; mTOR: mammalian target of rapamycin; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; NK cells: natural killer cells; PD1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; PI3K/Akt: phosphatidylinositol 3-kinase/protein kinase B pathway; S-S: disulfate bond; TCR: T-cell receptor; Tregs: T regulatory cells.