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.

Triple-Negative Breast Cancer: Intact Mismatch Repair and Partial Co-Expression of PD-L1 and LAG-3

“…LAG-3 is considered the paramount target next to PD-1. At least 13 anti-LAG-3 reagents have been developed to date ( 40 ).…”

Tumor Mutational Burden and Survival in Papillary Renal Cell Carcinoma Patients

“…These results indicate that the high in ltration of Tregs in low TMB tumors is associated with the high expression of LAG3, which may lead to the poor outcome in PRCC. Since LAG3 is now expected to be a highly promising target in cancer therapies [49], we believe that further research should be carried out to explore the value of LAG3 in the treatment of PRCC. It is known that an active immune response results in a better prognosis in PRCC.…”

Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression

“…LAG-3 conventionally binds to MHC II. however, there is also evidence of its interaction with galectin-3 (Gal-3), LSECtin, and fibrinogen like protein 1 (FGL1) [ 246 ]. LAG-3 acts as a TCR co-receptor that is upregulated following antigen exposure [ 247 ].…”