Multidimensional single-cell analysis reveals immune dysfunction and inflammatory response in Lymphatic malformations

Lymphatic malformations (LMs) are debilitating and life-threatening diseases. However, the immune phenotype of circulating cells and underlying molecular mechanisms in LMs remain poorly understood. Through single-cell transcriptome analysis, along with TCRs and BCRs profiling, we uncovered the impact of LMs on blood and pleural effusion. This included an expansion of pro-inflammatory monocytes and B cells, coupled with depletion of cytotoxic T and NK cells. CD14+ monocytes exhibited reduced REL and RFX5 transcription factor activity, correlating with impaired antigen presentation. Additionally, alterations in the clonality and diversity of TCRs and BCRs were observed in LMs. Moreover, monocyte CXCL16 interact with CXCR6 may be associated with inflammation, and upregulation of inhibitory checkpoint HLA-E:CD94-NKG2A potentially impaired NK cells’ activity. Notably, our study suggested S100A8 as a potential therapeutic target for LMs, demonstrating its pharmacological inhibition ameliorates pathological lymphatic malformation phenotype. Altogether, these findings delineate unique immunopathological mechanisms in LMs, offering insights for therapeutic development.