Targeting modulated vascular smooth muscle cells in atherosclerosis via FAP-directed immunotherapy
Junedh Amrute, In‐Hyuk Jung, Tracy Yamawaki, In-Hyuk Jung, Andrea Bredemeyer, Johanna Diekmann, Sikander Hayat, Xianglong Zhang, Devin L. Wakefield, Xianglong Zhang, Sidrah Maryam, Gyu Seong Heo, Steven Yang, Gyu Seong Heo, Steven Yang, Caroline Chou, Chen Wang, Kevin D. Cook, Atilla D. Kovács, Vishnu Chintalgattu, Danielle Pruitt, Jose Barreda, Nathan O. Stitziel, Paul Cheng, Y. Liu, Rafael Kramann, Daniel Kreisel, Roger S-Y Foo, Ingrid C. Rulifson, Roger S.-Y. Foo, David Grunert, Scott Martin, Jixin Cui, Thomas Quertermous, Frank M. Bengel, Simon Jackson, Chi-Ming Li, Brandon Ason, Kory J. Lavine, Brandon Ason, Kory J. Lavine
Abstract
Vascular smooth muscle cell (VSMC) diversification drives atherosclerotic coronary artery disease (CAD), but the mechanisms governing these cell state transitions remain unclear. We applied multiomic single-cell profiling, epitope mapping, and spatial transcriptomics across 27 human coronary arteries, identifying fibroblast activation protein (FAP) as a marker of modulated VSMCs. Lineage tracing in mice indicated that FAP + cells originate from Myh11 + VSMCs, and FAP positron emission tomography imaging in CAD patients showed plaque uptake. FAP + cell states resided in the macrophage-rich neo-intima. Therapeutically, we developed an anti-FAP bispecific T cell engager, which reduced plaque burden and remodeled the stromal–immune microenvironment through T cell clonal expansion. Our study delivers a single-cell and spatial atlas of human CAD, establishes FAP as a marker of modulated VSMCs, and highlights immunotherapy for lipid-independent targets.