TREM2介导MAC-1调控血管通透性促进卵巢癌腹水生成的作用机制研究

腹水是卵巢癌常见且预后差的并发症，成为治疗瓶颈。目前认为血管通透性增加是其形成的主要原因。我们前期通过对卵巢癌中免疫细胞的单细胞转录组分析发现：免疫球蛋白受体TREM2在卵巢癌组织的巨噬细胞中高表达，且敲低TREM2导致血管通透性增加；进一步发现：TREM2可通过JAK6/STAT3调节细胞间黏附分子ICAM1的受体MAC-1的表达水平，而ICAM1是已知的调控血管通透性的关键分子。由此提出假说：卵巢癌巨噬细胞TREM2可通过上调MAC-1水平提高内皮细胞通透性，从而促进腹水生成。本项目拟从细胞和动物水平阐明TREM2介导MAC-1调控血管通透性的分子机制；然后在卵巢癌动物模型中验证阻断该通路对血管通透性的抑制效果；最后在临床样本中探讨TREM2/MAC-1通路分子与腹水生成和疾病进展的关联性。该研究将首次阐明巨噬细胞TREM2对血管通透性的调控机制，为腹水的免疫治疗提供新策略。

Ascites is a common complication of ovarian cancer with poor prognosis and thus becomes a treatment bottleneck. At present, it is believed that increased vascular permeability is the main cause of ascites formation. Through single-cell transcriptome analysis of immune cells in ovarian cancer, we found that the immunoglobulin receptor TREM2 was highly expressed in macrophages in the tumor tissue, and knockdown of TREM2 led to the enhancement of endothelial barrier function. Furthermore, we revealed that TREM2 could regulate the expression of MAC-1, a receptor for the intercellular adhesion molecule (ICAM1), through JAK6/STAT3 pathway and ICAM1 is known to be a key regulator of vascular permeability. Therefore, we hypothesize that TREM2 in the ovarian cancer macrophages could promote vascular permeability by upregulating the expression of MAC-1, thereby induce ascites production. Here we aim to elucidate the molecular mechanism of TREM2-mediated, MAC-1-dependent regulation of vascular permeability in vitro and in vivo. Moreover, the inhibitory effect of blocking the TREM2/MAC-1 pathway on vascular permeability will be validated in the ovarian cancer animal model. Lastly, the association between TREM2/MAC-1 pathway molecules and ascites formation as well as disease progression will be explored in clinical samples. This study will uncover the role of TREM2 in the regulation of vascular permeability, and provide a new strategy for the immunotherapy of ascites.