LAG-3 is an inhibitory receptor expressed by exhausted T cells and is considered a promising immunotherapeutic target. However, important questions regarding its biology and mechanism of action still exist. This Perspective discusses the gaps in understanding LAG-3 biology and the current debates and focus on five key topics, including its ligands, signaling and mechanism of action, cell-specific functions, importance in different disease settings, and the development of novel therapeutics.
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. LAG-3 is a T cell inhibitory receptor with a lot of promise as a target for immunotherapy, but considerable research will be needed to fully understand the nuances of this receptor and how best to target it, as outlined in this Perspective.
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