PD-1/PD-L1通路抑制剂联合VEGF-Trap治疗卵巢癌的分子机制研究

Although cytoreductive surgery combined with chemotherapy can benefit patients with ovarian cancer, most patients will still be progressive. In the process of tumorigenesis and development, tumor immune escape is generated. Therefore, it is an urgent need to study the immune microenvironment of ovarian cancer and the corresponding molecular targeted therapy. Vascular endothelial growth factor (VEGF), a proangiogenic molecule produced by tumors, it is unclear, whether VEGF can regulate PD-1 (programmed cell death-1) expression and other inhibitory checkpoints in tumor microenvironment. However, PD-1 and its ligands, PD-L1 - mediated signaling pathways in the regulation of immune homeostasis playing a key role. Our previous study found that PD-1 / PD-L1 pathway plays an important role in tumor prognosis. So far, there is no research about PD-1/PD-L1 pathway blockade combined with VEGF-Trap for the treatment of ovarian cancer. Therefore, this program intends to confirm the role of VEGF in the development and progression of ovarian cancer and explore the signal transduction mechanism and elucidate the inhibition of VEGF, how to alter ovarian cancer immune microenvironment. In view of these results, optimized the effect of VEGF-Trap, for the first time to explore in vitro and in vivo effect of the PD-1/PD-L1 pathway blockade combined with VEGF-Trap and provide a theoretical basis and new treatment idea for the combined therapy of ovarian cancer.

尽管肿瘤细胞减灭术联合化疗可使卵巢癌患者受益，但多数患者仍会进展。在肿瘤发生发展过程中，肿瘤细胞可产生免疫逃逸，因此，迫切需要研究卵巢癌免疫微环境及相应的分子靶向治疗。VEGF是常见的肿瘤微环境中分泌的促血管生成因子，目前尚不清楚，VEGF能否调节肿瘤微环境中程序性细胞死亡受体-1 ( PD-1) 等抑制性分子的表达，而PD-1及其配体PD-L1介导的信号通路在调控机体免疫稳态中起关键作用，我们前期研究发现该通路在肿瘤预后中起重要作用。迄今为止，国内外尚无PD-1/PD-L1通路抑制剂联合VEGF靶向抑制剂（VEGF-Trap）治疗卵巢癌的相关研究。因此，本课题拟证实VEGF在卵巢癌进展中的作用并探讨其信号传导机制; 阐明靶向抑制VEGF如何改变卵巢癌免疫微环境; 首次探讨PD-1/PD-L1通路抑制剂联合VEGF-Trap 在卵巢癌的体内外效果，为联合治疗提供理论依据和新的治疗思路。

在肿瘤发生发展以及治疗过程中，肿瘤细胞可产生免疫逃逸，因此，迫切需要研究卵巢癌分子靶向治疗对于免疫微环境的影响。VEGF是常见的肿瘤微环境中分泌的促血管生成因子，通过研究我们证实VEGF抑制剂可诱导免疫耐受，上调程序性细胞死亡受体配体-1 ( PD-L1)并且通过IFNGR-IFN-γ通路，而PD-1及其配体PD-L1介导的信号通路在调控机体免疫稳态中起关键作用。迄今为止，国内外尚无PD-1/PD-L1通路抑制剂联合VEGF靶向抑制剂治疗卵巢癌的相关研究。因此，本课题证实VEGF在卵巢癌进展中的作用并探讨其信号传导机制;首次 阐明靶向抑制VEGF如何改变卵巢癌免疫微环境; 首次探讨PD-1/PD-L1通路抑制剂联合VEGF抑制剂在卵巢癌的体内外效果，为联合治疗提供理论依据和新的治疗思路。