PLIN2+卵巢癌腹水相关巨噬细胞的促肿瘤转移机制及可视化靶向诊疗的研究

本项目对应指南研究方向2：“恶性肿瘤演进过程中肿瘤异质性和微环境的可视化及其诊疗新策略”。多数卵巢癌患者在确诊时伴有腹水，腹水不但严重影响患者生活质量，还直接决定其治疗转归。目前尚无针对腹水的有效治疗且缺乏早期诊断，而靶向腹水免疫微环境的关键组分可能同时实现诊断、干预及治疗监测。申请人通过单细胞转录组测序首次发现了PLIN2+腹水巨噬细胞亚群，并进一步证明巨噬细胞PLIN2高表达与卵巢癌预后差相关，且促进肿瘤细胞迁移。由此提出假设：通过靶向PLIN2+卵巢癌腹水相关巨噬细胞可抑制肿瘤转移，同时实现对疾病的精准诊疗及可视化监测。本项目拟通过体内外实验明确腹水相关巨噬细胞PLIN2对肿瘤转移的作用及其分子机制，并利用自主研发的M2型巨噬细胞靶向载体递送PLIN2 siRNA进行靶向治疗，同时设计新型铜-64标记PLIN2抗体的PET示踪剂，实现对卵巢癌腹水相关巨噬细胞的早期检测和靶向治疗可视化。

This project corresponds to the Research Direction 2 in the Guide, which is “the visualization and new strategy of diagnosis and treatment of tumor heterogeneity and microenvironment in the evolution of malignant tumor". Currently there is no effective treatment for ascites and there is a lack of early diagnosis. Targeting key components in the ascites immune microenvironment may simultaneously diagnose, intervene and monitor the treatment. We identified for the first time a group of PLIN2+ macrophages in the ascites through single-cell RNA-sequencing, and further demonstrated that high expression of macrophage PLIN2 was associated with poor prognosis of ovarian cancer and could promote tumor cell migration. Therefore, we hypothesize that through targeting PLIN2+ ovarian cancer ascites-associated macrophages we could not only inhibit tumor metastasis, but also achieve accurate diagnosis and treatment as well as disease visualization. This project aims to elucidate the role and the mechanism of PLIN2 in ascites-associated macrophages on tumor metastasis through in vitro and in vivo experiments, and to use self-developed M2 macrophage-targeting carrier delivering PLIN2 siRNA for targeted therapy, while designing a new copper-64 tagged PLIN2 antibody as PET tracer, to achieve the early detection and targeted therapy visualization of ovarian cancer ascites-associated macrophages.