癌症免疫疗法
细胞生物学
癌细胞
免疫疗法
T细胞
生物
细胞
受体
免疫系统
癌症研究
免疫检查点
单克隆抗体
癌症
免疫学
抗体
生物化学
遗传学
作者
Kushal Prajapati,Chuan Yan,Qiqi Yang,Steven Arbitman,Daniel P. Fitzgerald,Sasan Sharee,Jahangheer Shaik,Jason Bosiacki,K. Myers,Ana Paucarmayta,Dorothy M. Johnson,Thomas O’Neill,Subrata Kundu,Zachary Cusumano,Solomon Langermann,David M. Langenau,Shashank J. Patel,Dallas B. Flies
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2024-03-01
卷期号:10 (9)
标识
DOI:10.1126/sciadv.adj4698
摘要
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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