The immune checkpoint receptor LAG3: Structure, function, and target for cancer immunotherapy

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• Lymphocyte activation gene 3 protein (LAG3) is an immune checkpoint receptor highly expressed on exhausted T cells.
• LAG3 binding to ligands like MHC class II inhibits T cell function in the tumor microenvironment.
• LAG3 is a significant target for cancer immunotherapy, with numerous anti-LAG3 monoclonal antibodies (mAbs) in clinical development.

Purpose of the Study:

• To review the molecular basis of LAG3 function using recent structural data.
• To discuss LAG3 interactions with its ligands, including MHC class II, FGL1, and TCR-CD3.
• To examine the development and mechanisms of anti-LAG3 mAbs for cancer immunotherapy and potential applications in autoimmune diseases.

Main Methods:

• Review of recent crystal and cryo-electron microscopy (cryo-EM) structures of LAG3.
• Analysis of published data on LAG3 interactions with known and novel ligands.
• Examination of clinical trial data for anti-LAG3 monoclonal antibodies.

Main Results:

• Recent structural studies provide insights into the molecular mechanisms of LAG3-ligand interactions.
• LAG3 interacts with MHC class II, FGL1, and TCR-CD3, with ongoing debate regarding their relative importance.
• Various anti-LAG3 mAbs are in clinical trials, targeting different LAG3 interactions and dimerization.

Conclusions:

• Understanding LAG3's molecular interactions is crucial for developing effective cancer immunotherapies.
• Targeting LAG3 with mAbs offers a promising strategy for cancer treatment, with potential for modulating autoimmune diseases.
• Future therapeutic strategies may involve mAbs that block LAG3 activity or enhance its inhibitory function.