ArticleScience advances2024
The FLRT3-UNC5B checkpoint pathway inhibits T cell-based cancer immunotherapies.
Article in Science advances, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 2 citations in OpenAlex.
- Targeting Oncomucin-Driven Immunosuppression Improves the Efficacy of K-rasGastroenterology · 2026Article
- UNC5B activates hepatic stellate cells and promotes liver fibrosis via FAK.Cell communication and signaling : CCS · 2026Article
- The neuro-vascular-immune triad: the interactive network in the tumor microenvironment.Cell communication and signaling : CCS · 2026Review
- Spatial transcriptomic analysis of 4NQO-induced tongue cancer revealed cellular lineage diversity and evolutionary trajectory.Frontiers in oncology · 2025Article
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cancers exploit coinhibitory receptors on T cells to escape tumor immunity, and targeting such mechanisms has shown remarkable clinical benefit, but in a limited subset of patients. We hypothesized that cancer cells mimic noncanonical mechanisms of early development such as axon guidance pathways to evade T cell immunity. Using gain-of-function genetic screens, we profiled axon guidance proteins on human T cells and their cognate ligands and identified fibronectin leucine-rich transmembrane protein 3 (FLRT3) as a ligand that inhibits T cell activity. We demonstrated that FLRT3 inhibits T cells through UNC5B, an axon guidance receptor that is up-regulated on activated human T cells. FLRT3 expressed in human cancers favored tumor growth and inhibited CAR-T and BiTE + T cell killing and infiltration in humanized cancer models. An FLRT3 monoclonal antibody that blocked FLRT3-UNC5B interactions reversed these effects in an immune-dependent manner. This study supports the concept that axon guidance proteins mimic T cell checkpoints and can be targeted for cancer immunotherapy.
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Registered trials
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