The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy

Abstract

Cancer immunotherapy and tumor microenvironment have been at the forefront of research over the past decades. Targeting immune checkpoints especially programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) has made a breakthrough in treating advanced malignancies. However, the low response rate brings a daunting challenge, changing the focus to dig deeply into the tumor microenvironment for alternative therapeutic targets. Strikingly, the inhibitory immune checkpoint lymphocyte activation gene-3 (LAG-3) holds considerable potential. LAG-3 suppresses T cells activation and cytokines secretion, thereby ensuring immune homeostasis. It exerts differential inhibitory impacts on various types of lymphocytes and shows a remarkable synergy with PD-1 to inhibit immune responses. Targeting LAG-3 immunotherapy is moving forward in active clinical trials, and combination immunotherapy of anti-LAG-3 and anti-PD-1 has shown exciting efficacy in fighting PD-1 resistance. Herein, we shed light on the significance of LAG-3 in the tumor microenvironment, highlight its role to regulate different lymphocytes, interplay with other immune checkpoints especially PD-1, and emphasize new advances in LAG-3-targeted immunotherapy.

Keywords: cancer immunotherapy; immune checkpoint; lymphocyte activation gene-3; tumor microenvironment.

Figure 1. Tumor microenvironment and immune checkpoints

In the TME, APCs present tumor antigens to naïve T cells and induce T-cell activation. The MHC and TCR signaling pathway provide the first signal for T-cell activation, while co-inhibitory immune checkpoints collaborate to suppress T-cell activation in the TME. Immune checkpoints are presented on T cells. Ligands are expressed on APCs, tumor cells and other stromal cells, such as CAFs and MDSCs. Abbreviations: TME = tumor microenvironment; APCs = antigen presenting cells; MDSCs = myeloid-derived suppressor cells; CAFs = cancer-associated fibroblasts; MHC = major histocompatibility complex; TCR = T-cell receptor; PD-1 = programmed death 1; PD-L1 = programmed cell death ligand-1; PD-L2 = programmed cell death ligand-2; LAG-3 = lymphocyte activation gene-3; CTLA-4 = cytotoxic T-lymphocyte antigen-4; VISTA = V-domain immunoglobulin-containing suppressor of T-cell activation; HHLA2 = human endogenous retrovirus-H long terminal repeat-associating protein 2; TIM-3 = T cell immunoglobulin and mucin domain 3; Gal-9 = Galectin-9; MDSCs = myeloid-derived suppressor cells

Figure 2. LAG-3 signaling and the interplay with other immune checkpoints

The interaction of LAG-3 with MHC-II prohibits the binding of the same MHC molecule to a TCR and CD4, thus suppressing TCR signal. LAG-3 transmits an inhibitory signal via the KIEELE motif in the cytoplasmic tail. Crosslinking of LAG-3 and CD3/TCR complex can impair T cell proliferation, cytokines secretion, and calcium ion fluxes. LAG-3 also interacts with two novel ligands postulated, Gal-3 and LSECtin, expressed on melanoma cells to modulate CD8⁺ T-cell function within the TME. Strikingly, LAG-3 inhibits T-cell activation collectively with other immune checkpoints, especially PD-1. Antagonist antibodies targeting inhibitory immune checkpoints can restore T-cell function and have shown benefits in active clinical trials. Abbreviations: APCs = antigen presenting cells; MHC = major histocompatibility complex; TCR = T-cell receptor; PD-1 = programmed death 1; PD-L1 = programmed cell death ligand-1; LAG-3 = lymphocyte activation gene-3; CTLA-4 = cytotoxic T-lymphocyte antigen-4; Gal-3 = Galectin-3; LSECtin = Liver sinusoidal endothelial cell lectin.