Targeting modulated vascular smooth muscle cells in atherosclerosis via FAP-directed immunotherapy.
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| Title: | Targeting modulated vascular smooth muscle cells in atherosclerosis via FAP-directed immunotherapy. |
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| Authors: | Amrute, Junedh M. (AUTHOR), Jung, In-Hyuk (AUTHOR), Yamawaki, Tracy (AUTHOR), Lin, Wen-Ling (AUTHOR), Bredemeyer, Andrea (AUTHOR), Diekmann, Johanna (AUTHOR), Hayat, Sikander (AUTHOR), Zhang, Xianglong (AUTHOR), Wakefield, Devin L. (AUTHOR), Luo, Xin (AUTHOR), Maryam, Sidrah (AUTHOR), Heo, Gyu Seong (AUTHOR), Yang, Steven (AUTHOR), Lee, Chang Jie Mick (AUTHOR), Wang, Chen (AUTHOR), Chou, Caroline (AUTHOR), Kuppe, Christoph (AUTHOR), Cook, Kevin D. (AUTHOR), Kovacs, Atilla (AUTHOR), Chintalgattu, Vishnu (AUTHOR) |
| Source: | Science. 4/2/2026, Vol. 392 Issue 6793, p1-18. 18p. |
| Subjects: | Atherosclerosis, Immunotherapy, Vascular smooth muscle, Bispecific antibodies, RNA sequencing, Atherosclerotic plaque, Proteins, Cell analysis |
| 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. Editor's summary: Atherosclerosis is characterized by the buildup of lipid-containing plaque in blood vessels including coronary arteries and is a leading cause of death worldwide. The mainstay of therapy is lipid-lowering agents such as statins, which help but do not always fully prevent disease progression and mortality. To gain further insight into the biology of atherosclerotic plaques, Amrute et al. performed single-cell spatial transcriptomics on coronary arteries from people with and without atherosclerosis. This analysis helped identify smooth muscle cells expressing fibroblast activation protein as a major culprit in blood vessel plaque formation. Immunotherapy using a bispecific T cell engager (BiTE) against this protein reduced the atherosclerotic plaque burden in mouse models, suggesting a potential therapeutic strategy. —Yevgeniya Nusinovich INTRODUCTION: Atherosclerosis is a leading cause of cardiovascular disease and mortality, which is characterized by accumulation of lipid-rich vascular plaques that contain diverse populations of stromal and immune cells. Preclinical studies have demonstrated that during atherogenesis, vascular smooth muscle cells (VSMCs) undergo a phenotypic shift and give rise to populations of modulated SMCs (modSMCs) that comprise the neo-intima. Genome-wide association studies have identified numerous genetic variants linked to coronary artery disease, many of which regulate genes expressed in VSMCs, highlighting the therapeutic potential of targeting VSMCs and their phenotypic transitions. Notably, major gaps remain in the field's mechanistic understanding of modSMC specification and contribution to plaque progression. RATIONALE: Advances in single-cell multiomics and spatial transcriptomics have enabled high-resolution profiling of healthy and diseased human tissues and provided an opportunity to map cell types within their anatomical context. During atherosclerosis progression, immune infiltration and VSMC diversification reshape the media and intimal compartments and drive neointimal growth and plaque instability. Comprehensive single-cell and spatial datasets of human coronary artery disease capturing these events are lacking. We performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell spatial transcriptomics on healthy and diseased human coronary arteries. We further leveraged mouse models and antibody-based therapeutics to dissect the origin of and target modSMCs in vivo. RESULTS: We identified fibroblast activation protein (FAP) as a marker of modSMCs located within the neo-intima in humans and mice. Using spatial transcriptomics, we revealed that FAP+ modSMCs reside within a macrophage-rich cellular neighborhood, which contributes to their specification. Genetic lineage tracing demonstrated that FAP+ modSMCs arise from quiescent VSMCs. To explore the therapeutic potential of targeting FAP+ modSMCs in atherosclerosis, we developed a half-life extended anti-FAP bispecific T cell–engaging antibody (BiTE) that harnesses T cell cytotoxicity with optimized pharmacodynamics to selectively eliminate FAP-expressing cells. Although BiTE technology has been extensively investigated in oncology to direct T cells against tumor-associated antigens, its application to cardiovascular disease is unexplored. BiTE treatment resulted in a marked reduction in plaque burden across mouse atherosclerosis models, suggesting that immunotherapeutic depletion of FAP+ modSMCs may be a viable therapeutic strategy for atherosclerosis. Finally, by leveraging single cell RNA sequencing, we observed that anti-FAP BiTEs favorably remodeled the cellular and immune cell architecture of the plaques, which was associated with emergence of clonal T cell populations. CONCLUSION: Collectively, this work provides a comprehensive single-cell and spatially resolved map of human coronary artery disease, identifies FAP as a marker of modSMCs, and introduces BiTE-based immunotherapy as a potential strategy for targeting atherosclerotic plaques by selectively depleting precise disease-associated VSMC states. Targeting FAP+ VSMCs reduces plaque burden.: (A) Single-cell and spatial multiomics map of human coronary arteries in health and disease. (B) FAP+ cells in the plaque can be noninvasively imaged in patients and are derived from VSMCs. (C) In vivo anti-FAP BiTE therapy remodels the vascular microenvironment and reduces atherosclerotic plaque burden. FAP, fibroblast activation protein; VSMCs, vascular smooth muscle cells; BiTE, bi-specific T cell engager. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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