LAG-3 is a promising inhibitory immune checkpoint for antitumor immunotherapy

ABSTRACT

Introduction

Lymphocyte activation gene-3 (LAG-3) is a member of the immunoglobulin superfamily. Engagement of LAG-3 by its ligands to trigger downstream signaling can inhibit immune responses and regulate the pathogenesis of many diseases, including cancer and inflammatory diseases.

Areas covered

We used keywords to search for relevant publications in PubMed and information on websites. After systematic analysis, we discuss the biological characteristics of LAG-3 and its ligands, LAG-3 related signaling, its roles in the pathogenesis of tumors, and its blockages for the treatment of cancers, as well as current challenges and future directions of research.

Expert opinion

Although the mechanisms underlying the action of LAG-3/ligand-related signaling in tumor development are not fully understood, advances in scientific research and LAG-3-based immunotherapies are promising. Further studies to explore its biological roles and molecular mechanisms may aid in developing new LAG-3- and ligand-based therapeutic drugs to benefit patients with different types of cancers.

KEYWORDS:

• LAG-3
• T cells
• tumor
• immune checkpoint
• immunotherapy

Article highlights

• LAG-3 is an immune checkpoint receptor on immunocompetent cells or becomes a soluble molecule (sLAG-3) in circulation.

• Several ligands for LAG-3 have been identified, and engagement of LAG-3 by MHC-II inhibits effector T cell function but promotes Treg activity.

• Engagement of LAG-3 by its ligand may, through its cytoplasmic domain, interact with LAP or others to modulate TCR-related signaling in effector T cells. However, the precise molecular mechanisms underlying LAG-3-related signaling in T cell activity have not yet been elucidated.

• There are many LAG-3 specific inhibitors, such as anti-LAG-3 antibodies available in clinical trials, particularly for testing the efficacy of the combination of anti-LAG-3 antibodies and anti-PD-1 antibodies.

• The first phase II/III clinical trial has brought promise that the combination of anti-LAG-3 antibodies and anti-PD-1 antibodies prolongs progression-free survival of melanoma patients.

• There are many issues that remain to be addressed, and further studies in this field may help uncover new therapeutic targets and regimens for the treatment of patients with cancer.

Conflict of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer review

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors have no funding to report.