血管内皮生长因子-A（VEGF-A）调节胶质母细胞瘤（GBM）血管的生成，但VEGF-A单抗治疗GBM患者的疗效有限，原因尚不明确。我们前期研究发现：VEGF-A单抗治疗GBM所致的调节性T细胞（Tregs）免疫逃逸是限制其疗效的重要机制之一。我们根据GITR通路对Tregs和CD8+T细胞的不同作用提出假设：GITR激活性单抗（DTA-1）能够逆转VEGF-A单抗所致的Tregs免疫逃逸，增强VEGF-A单抗的疗效。本项目利用DTA-1、VEGF-A单抗治疗GBM荷瘤鼠，记录生存期；提取肿瘤和全身免疫器官中的T细胞，利用流式细胞术、RT-qPCR、免疫荧光、转录组测序和生信分析等研究方法，证实DTA-1能够减少Tregs的数量，减弱免疫抑制功能，并增强CD8+T细胞的肿瘤杀伤能力。从肿瘤免疫角度阐明DTA-1逆转VEGF-A单抗所致的Tregs免疫逃逸的机制，为临床应用提供依据。

Vascular endothelial growth factor-A (VEGF-A) regulates angiogenesis for glioblastoma (GBM). However, it is not fully understood why the clinical efficacy of VEGF-A monoclonal antibody (mAb) in the treatment of GBM is limited. Our data suggested that regulatory T cells (Tregs) mediated tumor immunoescape is one of the most important reasons for poor curative effect in the treatment of GBM by VEGF-A mAb. Based on the different effects of the activation GITR pathway on Tregs and CD8+ T cells, we hypothesize that GITR agonistic antibody (DTA-1) enhances the therapeutic effects of VEGF-A mAb by inhibiting Tregs mediated tumor immunoescape induced by VEGF-A mAb. To confirm these hypotheses, DTA-1 and VEGF-A mAb will be administered to GBM tumor-bearing mice, and the survival data will be recorded. Furthermore, T cells in tumors and systemic immune organs will be isolated and analyzed by flow cytometry, RT-qPCR, immunofluorescence, transcriptome sequencing, and bioinformatics analysis. We hope to prove that DTA-1 could reduce the number of Tregs, resulting in decreased immunosuppression. Meanwhile, DTA-1 could enhance the anti-tumor efficacy of CD8 + T cells. From an immunotherapy perspective, the project aims to elucidate that DTA-1 reverses Tregs mediated tumor immunoescape induced by VEGF-A mAb, providing evidence for the combination strategy of DTA-1 and VEGF-A in GBM.