血管生成素样蛋白2新受体F11r在血管生成及肿瘤免疫治疗中的机制和应用研究

Angiogenesis plays essential roles in the development of tumor, and was considered to be an important target in tumor treatment. It was well known that Angiopoietin-like-protein 2 (Angptl2) regulates angiogenesis, but its related receptor and the downstream signaling remain unclear. In our preliminary experiments, by the high-through put screening with all membrane protein libraries, we identified that F11r is a specific receptor of Angptl2 to regulate angiogenesis. In this project, we intend to figure out the interaction mechanism between Angptl2 to F11r and its downstream signaling, and explore its roles in tumor development. Moreover, abnormal tumor vessel will greatly affect tumor immune microenvironment, leading to the decrease of the therapeutic outcome during tumor immunotherapy. Such as that we had successfully developed a STING-activating synthetic nanovaccine with highly effective anti-tumor efficacy against various solid tumors; however, the efficacy gradually decreased if we immunized the mice in tumor late stage. So we will explore the effects of blocking F11r-Angptl2 interaction in tumor vascular normalization, hope to reverse the suppressive immune microenvironment in tumor, to obtain an optimized combination strategy for tumor immune therapy.

血管生成是肿瘤发生与发展中的关键环节，也是肿瘤治疗的重要靶点。血管生成素样蛋白2（Angiopoietin-like-2，Angptl2）促血管生成功能已熟知，但其受体及下游作用机制并不清楚。我们通过对膜蛋白文库大量筛选，已得到与Angptl2相互作用的受体F11r，并在Angptl2介导的血管生成中发挥关键作用。我们拟深入研究Angptl2与F11r特异结合的分子机理，并进一步探索阻断该通路对肿瘤发生和发展的影响，以期获得针对肿瘤血管生成的新的治疗靶点。由于异常的肿瘤血管会阻碍肿瘤免疫的正常进行，如何改善肿瘤微环境也是当前肿瘤免疫治疗的关键。我们已开发一株STING依赖的纳米疫苗，在多种肿瘤模型中取得了良好疗效，但在肿瘤生长后期介入，效果会逐渐降低。我们也将研究阻断F11r信号通路对肿瘤血管正常化以及肿瘤免疫微环境的影响，以期逆转肿瘤免疫抑制微环境，开发更好的基于纳米疫苗的联合治疗策略。

免疫检查点抑制剂（Immune checkpoint blocker, ICB），如 CTLA4（Cytotoxic T-lymphocyte-associated protein 4）或 PD1（Programmed cell death 1）抗体，已经在晚期黑色素瘤、非小细胞肺癌、肾癌等多种肿瘤病人中取得了良好的治疗效果， 但目前仅限于一小部分病人。这种选择性疗效的内在机制仍不清楚，而且，如何预测免疫检查点抑制剂的治疗效果仍是一个急需解决的问题。在我们的研究中发现，低剂量的GEM节律化疗(met-GEM)可以诱导肿瘤血管正常化，可以将对CTLA4或者PD-1抗体治疗不敏感的小鼠乳腺肿瘤转化为治疗敏感的肿瘤；节拍化疗 met-GEM与免疫检查点抑制剂的联合使用可以提高肿瘤浸润的T淋巴细胞的比例，并提高抗癌基因的表达。该结果提示，改善血管的灌注功能，可以提高免疫检查点抑制剂的作用效果。