COX-2/PGE2促进骨肉瘤干细胞干性及免疫逃逸的机制研究

骨肉瘤呈COX-2高表达，尤其是骨肉瘤干细胞COX-2表达增高141倍，并维持骨肉瘤干细胞干性。前期研究发现，COX-2/PGE2能够抑制T细胞活性，减弱免疫系统对骨肉瘤干细胞的正常应答，导致肿瘤的免疫逃逸，但其作用机制不详。进一步研究发现COX-2抑制剂能够下调PI3K/Akt，β-catenin等表达，而β-catenin是树突状细胞（DC）中介导免疫逃逸的关键因子。我们推测，骨肉瘤干细胞中COX-2催化生成PGE2并分泌至肿瘤微环境，维持骨肉瘤干细胞干性，并与DC表达的PGE2受体（EPs）结合，通过调控β-catenin启动维甲酸（RA）信号通路，介导免疫逃逸。本项目拟研究COX-2/PGE2调控树突状细胞β-catenin/RA信号通路，发挥“免疫编辑”作用，致使免疫细胞极化偏移，抑制细胞毒性T淋巴细胞浸润，从而阐明COX-2/PGE2介导骨肉瘤干细胞干性及免疫逃逸的机制。

Osteosarcoma (OS) is the most common primary bone tumor in children and young adults, cancer stem cells (CSCs) play a major role in drug resistance and treatment failure. Osteosarcomas express COX-2 constitutively, and COX-2 expresses 141-fold more in CSC spheres. COX-2/PGE2 induces CSCs and immune evasion. Our group previous study showed COX-2/PGE2 inhibited T-cell activation and biological.responses, induced immune evasion. Meanwhile, COX-2 inhibitors could down-regulate activation of PI3K/Akt and β-catenin. β-catenin in dendritic cells plays a critical role in balancing immunity and tolerance. We hypothesize that in the tumor microenvironment (TME), COX-2/PGE2 actives β-catenin in dendritic cells,produces RA and induces immune evasion. This project aims to study COX-2/PGE2 of osteosarcoma stem cells induces immune evasion through β-catenin/RA signaling in dendritic cells, COX-2/PGE2 plays “Cancer mmunoediting”, causes immune cell polarization, inhibits cytotoxic T lymphocyte (CTL) infiltration, to clarify the mechanism of osteosarcoma stem cells in the immune evasion, which may provide new strategy in clinical immunotherapy of cancer.