The Fibronectin-ILT3 Interaction Functions as a Stromal Checkpoint that Suppresses Myeloid Cells

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Suppressive myeloid cells impede antitumor immunity by inhibiting T-cell responses.
• Immunoglobulin-like transcript 3 (ILT3), also known as LILRB4, is highly expressed on tumor-associated myeloid cells, promoting their suppressive function.
• The specific ligand engaging ILT3 in the tumor microenvironment, leading to myeloid cell suppression, was previously unidentified.

Purpose of the Study:

• To identify the functional ligand for ILT3 within the tumor microenvironment.
• To investigate the role of the ILT3-ligand interaction in myeloid cell polarization and tumor immunity.
• To explore the therapeutic potential of blocking the ILT3-ligand interaction.

Main Methods:

• A screening approach was employed to identify functional ligands for ILT3.
• The interaction between fibronectin and ILT3 was characterized.
• The effects of an ILT3-specific antibody blocking this interaction were assessed.
• Human tumor explants were treated ex vivo with anti-ILT3 antibodies.

Main Results:

• Fibronectin was identified as a functional ligand for ILT3.
• The interaction between fibronectin and ILT3 polarized myeloid cells towards a suppressive state.
• Treatment with an ILT3-specific antibody reversed these suppressive effects by blocking the fibronectin-ILT3 interaction.
• Ex vivo treatment of human tumor explants with anti-ILT3 reprogrammed myeloid cells to a stimulatory phenotype.

Conclusions:

• The ILT3-fibronectin interaction acts as a "stromal checkpoint", where the extracellular matrix actively suppresses myeloid cells.
• Blocking this interaction can reprogram tumor-associated myeloid cells to a stimulatory phenotype.
• Targeting the ILT3-fibronectin axis holds potential for enhancing antitumor T-cell responses and improving cancer immunotherapy.