乏氧微环境中VEGFR分子靶向药物对DCs功能的影响及机制

Angiogenesis is essential for tumor growth and metastatic dissemination.Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling pathway is involved in tumor angiogenesis, and thus become the target of anti-tumor therapy. Currently, three agents targeting this pathway (sunitinib, sorafenib, pazopanib) are FDA approved for the treatment of advanced renal cell carcinoma.Although treatments prolong progression-free survival of patients, there are still low response rate, the occurrence of acquired resistance and other issues to be solved shortly. Local tumor immune response status can significantly affect tumor progression. Maturation of dendritic cells (DCs) is crucial for initiation and regulation of primary immune responses, and VEGF signaling pathway is one of the critical path to maintain DCs' function. However, the effect of VEGF/VEGFR pathway inhibition on the anti-tumor immune response induced by DCs is unclear. On the basis of the preliminary work in present study, we will explore the impact of these agents on DCs VEGF / of VEGFR signaling activity and related signaling pathways under normoxic and hypoxic conditions, inquire into the molecular mechanisms of its influence on the biological characteristics of DCs. The results provide a theoretical basis for the immune mechanism involved in acquired resistance, and provide important information for the development of new antiangiogenic targeted agents.

血管新生是肿瘤生长和转移的基础，血管内皮生长因子(VEGF)及其受体(VEGFR)是肿瘤血管新生所涉及的主要信号通路，因此成为了抗肿瘤治疗的靶标。目前，三种针对该通路的分子靶向药物已应用于临床，延长了肿瘤患者的无进展生存期，但仍存在反应率较低、短期内发生获得性耐药等问题亟待解决。肿瘤局部免疫应答状态可显著影响肿瘤进展，树突状细胞(DCs)是启动和调控免疫应答的重要细胞，而VEGF信号通路也是维持DCs功能的关键通路之一。然而，关于干扰DCs VEGF/VEGFR通路对其抗肿瘤免疫应答诱导的影响尚不明确。本研究在前期工作的基础上，探讨常氧及乏氧下抗血管新生分子靶向药物对DCs VEGF/VEGFR信号活性及相关信号途径的影响，对DCs调控不同Th分化和趋化的影响，并分析其影响DCs生物学性状的分子机制。研究结果为该类药物耐药的免疫机制提供理论基础，为抗血管新生分子靶向药物的开发提供重要信息。

血管新生是肿瘤生长和转移的基础，血管内皮生长因子(VEGF)及其受体(VEGFR)是肿瘤血管新生所涉及的主要信号通路，因此成为了抗肿瘤治疗的靶标。目前，三种针对该通路的分子靶向药物已应用于临床，延长了肿瘤患者的无进展生存期，但仍存在反应率较低、短期内发生获得性耐药等问题亟待解决。肿瘤局部免疫应答状态可显著影响肿瘤进展，树突状细胞(DCs)是启动和调控免疫应答的重要细胞，而VEGF信号通路也是维持DCs功能的关键通路之一。然而，关于干扰DCs VEGF/VEGFR通路对其抗肿瘤免疫应答诱导的影响尚不明确。本研究在前期工作的基础上，探讨常氧及乏氧下抗血管新生分子靶向药物对DCs VEGF/VEGFR信号活性及相关信号途径的影响，对DCs调控不同Th分化和趋化的影响，并分析其影响DCs生物学性状的分子机制。研究结果为该类药物耐药的免疫机制提供理论基础，为抗血管新生分子靶向药物的开发提供重要信息。