LAG-3: from molecular functions to clinical applications

Abstract

To prevent the destruction of tissues owing to excessive and/or inappropriate immune responses, immune cells are under strict check by various regulatory mechanisms at multiple points. Inhibitory coreceptors, including programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), serve as critical checkpoints in restricting immune responses against self-tissues and tumor cells. Immune checkpoint inhibitors that block PD-1 and CTLA-4 pathways significantly improved the outcomes of patients with diverse cancer types and have revolutionized cancer treatment. However, response rates to such therapies are rather limited, and immune-related adverse events are also observed in a substantial patient population, leading to the urgent need for novel therapeutics with higher efficacy and lower toxicity. In addition to PD-1 and CTLA-4, a variety of stimulatory and inhibitory coreceptors are involved in the regulation of T cell activation. Such coreceptors are listed as potential drug targets, and the competition to develop novel immunotherapies targeting these coreceptors has been very fierce. Among such coreceptors, lymphocyte activation gene-3 (LAG-3) is expected as the foremost target next to PD-1 in the development of cancer therapy, and multiple clinical trials testing the efficacy of LAG-3-targeted therapy are underway. LAG-3 is a type I transmembrane protein with structural similarities to CD4. Accumulating evidence indicates that LAG-3 is an inhibitory coreceptor and plays pivotal roles in autoimmunity, tumor immunity, and anti-infection immunity. In this review, we summarize the current understanding of LAG-3, ranging from its discovery to clinical application.

Keywords: adaptive immunity; immune tolerance.

Figure 1

Structure of LAG-3. (A) Schematic representation of LAG-3. CP, connecting peptide; D1-D4, domains 1-4; EL, extra loop; IC, intracellular. (B–D) Alignments of EL, CP, and IC. Amino acid sequences of EL (B), CP (C), and IC (D) are shown for indicated species. Amino acid residues conserved between human and mouse are colored in red for EL (B) and CP (C). Putative FxxL, KIEELE, and EX-repeat are boxed. Amino acid sequences of LAG-3 were retrieved from Ensembl.org.

Figure 2

Ligands of LAG-3. (A) LAG-3 selectively binds to stable pMHCII and inhibits the activation of CD4⁺ T cells that recognize stable pMHCII. (B) Reported non-MHCII ligands. LAG-3 has been reported to associate with FGL1, LSECtin, galectin-3, and α-synuclein fibrils. FGL1, fibrinogen-like protein 1; LSECtin, liver sinusoidal endothelial cell lectin; MHCII, major histocompatibility complex class II; pMHCII, peptide-MHCII complex; APC, antigen presenting cell; TCR, T cell receptor.