PGE2介导肺癌细胞诱导巨噬细胞功能极化的作用及机制研究

肿瘤演进过程中，肿瘤细胞与基质免疫细胞的相互作用备受关注。与正常巨噬细胞相比，肿瘤基质中的巨噬细胞处于功能极化状态、倾向于免疫抑制表型、促进肿瘤发生发展，但其机制不明。我们前期研究发现肺癌组织中大量巨噬细胞浸润且高表达程序性死亡蛋白配体PD-L1；肺癌细胞能诱导巨噬细胞高表达PD-L1和趋化因子CCL2，并与前列腺素E2（PGE2）密切相关。本研究通过建立肺癌细胞与巨噬细胞间接共培养模型，以抗体阻断、功能缺失、芯片杂交等技术探索PGE2介导癌细胞教育诱导巨噬细胞功能极化的作用、信号转导途径及巨噬细胞反哺癌细胞的关键因子；建立裸鼠肺癌细胞与巨噬细胞共移植模型及巨噬细胞清除肺癌细胞移植模型，探索癌细胞与巨噬细胞的互作关系；行肺癌临床组织标本相关因子检测进行验证。从基质免疫细胞角度阐明肺癌演进机理并诠释肺癌细胞与巨噬细胞之间的内在关系及其分子事件，为“再教育”巨噬细胞逆转肿瘤发生发展提供依据。

In the process of tumor development，the interaction between tumor cells and stromal immune cells is concerned. Compared with normal macrophages, macrophages in tumor stroma can be polarized to have an immunosuppressive phenotype which promotes tumor progression, but the mechanism is unclear. Our previous study found that a large number of macrophages infiltrate in lung cancer tissues with high expressions of the programmed death protein-ligand PD-L1. Lung cancer cells can induce macrophages to overexpress PD-L1 and chemokine CCL2 mediated by prostaglandin E2 (PGE2). This study aims to establish an in vitro indirect co-culture model of lung cancer cells and macrophages to investigate the mechanism of PGE2 in mediating the function polarization of macrophages induced by cancer cells via antibody blocking, Loss-of-Function technique, and chemokine chip hybridization and explore the critical factors for macrophage feeding back cancer cells. Establish a co-transplantation model of lung cancer cells and macrophages and macrophage deletion model of lung cancer cell transplantation in nude mice, and explore the interaction function between cancer cells and macrophages from the animal level. Immunofluorescence multiple staining was used to detect the related factors in lung cancer clinical tissues, and analyzed the indicators and correlation between clinicopathological parameters. The purpose is to elucidate the mechanism of lung cancer evolution from the perspective of immunity cells in tumor stroma and to interpret the fundamental relationship between lung cancer cells and macrophages and their molecular events in order to lay a foundation for the "re-education" of macrophages to kill lung cancer cells.