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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.

Citation

Kushal Prajapati, Chuan Yan, Qiqi Yang, Steven Arbitman, Daniel P Fitzgerald, Sasan Sharee, Jahangheer Shaik, Jason Bosiacki, Kayla Myers, Ana Paucarmayta, Dorothy M Johnson, Thomas O'Neill, Subhadip Kundu, Zachary Cusumano, Solomon Langermann, David M Langenau, Shashank Patel, Dallas B Flies. The FLRT3-UNC5B checkpoint pathway inhibits T cell-based cancer immunotherapies. Science advances. 2024 Mar;10(9):eadj4698

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PMID: 38427724

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