The FLRT3-UNC5B checkpoint pathway inhibits T cell–based cancer immunotherapies
Menée à l'aide de données du projet "The Cancer Genome Atlas", de lignées cellulaires, de modèles murins et de poissons-zèbres, cette étude met en évidence un mécanisme par lequel la protéine transmembranaire FLRT3 des cellules cancéreuses inhibe les immunothérapies anticancéreuses à base de lymphocytes T via le récepteur de guidage axonal UNC5B
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. FLRT3-UNC5B is an immune coinhibitory pathway that can be targeted to enhance T cell–based therapies.
Science Advances , article en libre accès, 2023