LAG-3 as the third checkpoint inhibitor

Abstract

Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor that is highly expressed by exhausted T cells. LAG-3 is a promising immunotherapeutic target, with more than 20 LAG-3-targeting therapeutics in clinical trials and a fixed-dose combination of anti-LAG-3 and anti-PD-1 now approved to treat unresectable or metastatic melanoma. Although LAG-3 is widely recognized as a potent inhibitory receptor, important questions regarding its biology and mechanism of action remain. In this Perspective, we focus on gaps in the understanding of LAG-3 biology and discuss the five biggest topics of current debate and focus regarding LAG-3, including its ligands, signaling and mechanism of action, its cell-specific functions, its importance in different disease settings, and the development of novel therapeutics.

Fig. 1 |. LAG-3 ligands.

a, LAG-3 ligands and their source. APC, antigen-presenting cell; MHCII, MHC class II. b, A timeline of LAG-3 ligand discovery.

Fig. 2 |. LAG-3 signaling.

The ‘EP’, KIEELE’ and ‘pS454/FxxL’ motifs are highly conserved motifs within the cytoplasmic tail of LAG-3. The ‘EP’ motif causes Lck to dissociate from CD4/CD8 by lowering the local pH. The mechanisms of action for ‘KIEELE’ and ‘pS454/FxxL’ are unknown. sLAG3, soluble LAG-3; MHC II, MHC class II.

Fig. 3 |. LAG-3-specific therapeutics.

Mode of action for antagonists that mainly function by blocking LAG-3 ligand interaction with bispecifcs, providing an opportunity to simultaneously block two ligands (left). Mode of action for agonists by enhancing LAG-3 clustering to TCR–CD3, blocking ADAM10/ADAM17 (ADAM10/17)-mediated cleavage of LAG-3 and bispecifics to induce allosteric changes (right). MHC II, MHC class II; mAb, monoclonal antibody.