Tertiary Lymphoid Organ-like Structures in Carotid Artery Plaques: A Breakthrough in Understanding Plaque Instability
Tertiary lymphoid organ-like structures in human atherosclerosis contribute to plaque instability. Xin Liu, on behalf of the XinLab team and our collaborators at Peking Union Medical College Hospital
Carotid artery plaques are a significant risk factor for atherosclerosis and various cardiovascular diseases. Driven by our passion for applying cutting‐edge genomic technologies to real-world clinical challenges, our team set out to unravel the cellular secrets hidden within these plaques. Using spatiotemporal omics and single‑cell sequencing, our research has revealed a previously unappreciated facet of plaque biology—clusters of immune cells that organize into structures strikingly similar to tertiary lymphoid organs (TLOs), commonly observed in tumor microenvironments.
Uncovering the Immune Landscape of Plaques
Our study employed high‑resolution spatial transcriptomics alongside single‑cell RNA sequencing to create a detailed atlas of the cellular composition within carotid plaques. The spatial data provided crucial context: we observed that in select regions of the plaque, immune cells—chiefly B cells and plasma cells—congregated into organized clusters. These structures bear a resemblance to TLS, suggesting that local immune responses may play a pivotal role in plaque progression and instability.
Further integrative analysis allowed us not only to map these cell assemblies but also to tease apart the key factors and signaling pathways that drive their formation. By combining molecular profiling with rigorous histopathological validation (using H&E staining), our data shows that plaques harboring TLS are more likely to be unstable and associated with adverse clinical symptoms. In other words, the presence of these organized immune cell clusters appears to contribute directly to the risk of subsequent cardiovascular events.
Significance of Our Findings
This discovery is particularly significant—it represents the first time that TLS-like structures have been definitively identified within carotid artery plaques. While similar structures have been observed in other atherosclerosis-related tissues, finding them in carotid plaques opens new avenues for understanding the adaptive immune responses that modulate plaque stability. Molecular evidence from our study suggests that the aggregation of B cells and plasma cells could instigate local inflammatory processes, destabilizing the plaque and thereby heightening the risk of clinical events.
Our work not only deepens our understanding of the immune system’s role in atherosclerosis but also uncovers new therapeutic targets. By pinpointing the molecular drivers of TLS formation within plaques, we pave the way for the development of interventions designed to stabilize these high-risk lesions, potentially preventing strokes and other cardiovascular complications.
A Collaborative Milestone
This study marks a major milestone in our research efforts. It was born out of a collaborative synergy between XinLab—a dynamic team led by Xin Liu at BGI—and our colleagues at Peking Union Medical College Hospital, spearheaded by Dr. Bao Liu. Significant contributions from Zhichao Lai, Deqiang Kong, Yue Wang, Qingsong Du, Ziqing Deng, and others exemplify the spirit of teamwork that drives breakthroughs in human disease research. For more information about our lab’s work, please visit www.xgenome.cn and our GitHub page liuxin-genomics.github.io.
Reflections on the Journey
No discovery, however groundbreaking, comes easily. Reflecting on the peer-review journey for this work, I recall a time of grueling scrutiny and intense revision. At moments, it felt like the hurdles were insurmountable; yet, the challenge was also deeply invigorating. In retrospect, every piece of feedback pushed us to refine our analyses and strengthen our conclusions. I find it fascinating how a rigorous review process ultimately enriches research—it shaped our study into something even more compelling and robust.
I am particularly grateful to Reviewer Klaus Ley, who not only provided incisive comments but also authored a thoughtful commentary on our work. His summary, available here, offers a distillation of our findings and an appreciation of their clinical implications. Such insights remind me that science, much like the fabled allegories of transformation, involves a process of refinement—a journey reminiscent of the Chinese fable of Sun Wukong being tempered in Laozi’s alchemy furnace until, in a dramatic reversal, the latent power bursts forth in unexpected ways.
Looking Ahead
Our discovery of TLS-like structures in carotid plaques is only the beginning. It not only underscores the critical role of local immune dynamics in cardiovascular disease but also opens exciting avenues for therapeutic intervention. XinLab remains dedicated to leveraging advanced genomic technologies in our quest to decode complex human diseases. I look forward to sharing more details about our ongoing research and the fascinating lessons learned from our continued exploration of the immune microenvironment in atherosclerosis.
We hope you find our journey as inspiring as we do. Stay tuned for more updates from XinLab, where cutting-edge genomics meets impactful discovery.