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Multidimensional single-cell analysis reveals immune dysfunction and inflammatory response in lymphatic malformations
Chunxiao Chen1,2, Wenhao Ju3, Xueying Li2
1Vascular Anomalies and Vascular Interventional Center, Capital Center for Children's Health, Capital Medical University, Capital Institute of Pediatrics, Beijing 100020, China.
Insights
Lymphatic malformations (LMs) involve immune cell dysfunction, with increased inflammatory monocytes and B cells, and decreased cytotoxic T and NK cells. Targeting S100A8 shows promise for treating these debilitating diseases.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Lymphatic malformations (LMs) are severe diseases with poorly understood immune system involvement.
- The molecular mechanisms driving immune dysregulation in LMs require further elucidation.
Purpose of the Study:
- To comprehensively characterize the immune cell landscape and molecular mechanisms in patients with LMs.
- To identify potential therapeutic targets for LMs based on immune profiling.
Main Methods:
- Integrated single-cell RNA, T-cell receptor, and B-cell receptor sequencing (scRNA-seq, scTCR-seq, scBCR-seq) were performed on peripheral blood and pleural effusion from LM patients.
- Functional analyses were conducted to assess antigen processing, presentation, and transcription factor activity.
- Repertoire analysis of T-cell receptors (TCRs) and B-cell receptors (BCRs) was performed.
Main Results:
- Expansion of pro-inflammatory CD14+CD16+ monocytes and atypical memory B cells, alongside a reduction in cytotoxic CD8+ T and NK cells.
- Impaired antigen processing/presentation in monocytes and dysregulated transcription factor activity were observed.
- Significant remodeling of TCR and BCR repertoires, altered CXCL16-CXCR6 signaling, and upregulation of HLA-E:CD94-NKG2A impacting NK cell activity.
- Identification of a pro-inflammatory monocyte program and S100A8 as a potential therapeutic target.
Conclusions:
- LMs are characterized by specific immune cell dysregulation, including monocyte and lymphocyte abnormalities.
- S100A8 is a promising therapeutic target, as its inhibition ameliorated the pathological LM phenotype.
- These findings provide critical insights into LM pathogenesis and potential avenues for treatment.
Abstract:
Lymphatic malformations (LMs) are debilitating and potentially life-threatening diseases. However, the immune phenotype of circulating cells and underlying molecular mechanisms in LMs remain poorly understood. Here, we performed integrated single-cell RNA, T-cell receptor, and B-cell receptor sequencing (scRNA-seq, scTCR-seq, and scBCR-seq) of peripheral blood and pleural effusion from patients with LMs to delineate their immune landscape. We identified an expansion of pro-inflammatory CD14+CD16+ monocytes and atypical memory B cells, accompanied by reduced cytotoxic CD8+ T and natural killer (NK) cells. Functional analysis revealed impaired antigen processing and presentation in CD14+ monocytes, and dysregulated transcription factor activity, potentially driving immune dysfunction. Additionally, LMs exhibited substantial remodeling of TCR and BCR repertoires, with shifts in clonality and diversity. Moreover, the CXCL16-CXCR6 interaction was associated with inflammatory responses, while upregulation of the inhibitory checkpoint HLA-E: CD94-NKG2A potentially contributed to impaired NK cell activity. Finally, we constructed a shared pro-inflammatory monocyte program and revealed S100A8 as a potential therapeutic target for LMs. We further demonstrated that S100A8 pharmacological inhibition could ameliorate the pathological phenotype of LMs. Collectively, our findings delineate cell type-specific immune dysregulation in LMs, offering insights for therapeutic development.
