The FLRT3-UNC5B checkpoint pathway inhibits T cell-based cancer immunotherapies

Area of Science:

• Immunology
• Neuroscience
• Oncology

Background:

• Cancer immune evasion often involves coinhibitory receptors on T cells.
• Current immunotherapies benefit only a subset of patients.
• Cancer cells may adopt developmental pathways, like axon guidance, to escape immune surveillance.

Purpose of the Study:

• To investigate if axon guidance pathways are exploited by cancer cells to inhibit T cell immunity.
• To identify specific axon guidance molecules involved in cancer immune evasion.
• To explore targeting these molecules for novel cancer immunotherapy strategies.

Main Methods:

• Utilized gain-of-function genetic screens to profile axon guidance proteins on human T cells.
• Identified fibronectin leucine-rich transmembrane protein 3 (FLRT3) and its receptor UNC5B.
• Tested FLRT3 function in humanized cancer models and evaluated antibody blockade efficacy.

Main Results:

• Identified FLRT3 as a T cell inhibitory ligand that binds to the UNC5B receptor, which is upregulated on activated T cells.
• FLRT3 expression in human cancers promoted tumor growth and impaired CAR-T and BiTE+T cell-mediated killing and infiltration.
• A monoclonal antibody blocking FLRT3-UNC5B interaction reversed tumor-promoting effects in an immune-dependent manner.

Conclusions:

• Axon guidance pathways, specifically the FLRT3-UNC5B axis, are mimicked by cancer cells to create immune checkpoints.
• Targeting the FLRT3-UNC5B interaction represents a promising strategy for enhancing cancer immunotherapy efficacy.