Journal Article Research Support, Non-U.S. Gov't Ppublish
PubMed: 38427724 DOI: 10.1126/sciadv.adj4698
The FLRT3-UNC5B checkpoint pathway inhibits T cell-based cancer immunotherapies.
Sci Adv 10(9):eadj4698
Authors: 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
Affiliations
- NextCure Inc. Beltsville, MD 20705, USA.
- Molecular Pathology and Cancer Center, Massachusetts General Hospital Research Institute, Charlestown, MA 02129, USA. Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
- Molecular Pathology and Cancer Center, Massachusetts General Hospital Research Institute, Charlestown, MA 02129, USA.
- Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
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.
MeSH
Cells, Biological Science Disciplines, Neoplasms, Axons, Axon Guidance, Immunotherapy, Immunity, T-Lymphocytes, Ligands