Jin Shasha, Li Tao, Liu Liu, Gao Ting, Zhang Tingting, Yuan Dingyi, Di Jianwen, Guo Zhanying, Luo Zhijie, Yuan Haoliang, Liu Jun
New Drug Screening and Pharmacodynamics Evaluation Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Br J Pharmacol. 2025 Mar;182(6):1306-1323. doi: 10.1111/bph.17404. Epub 2024 Dec 3.
The current therapy cannot meet the needs of glioblastoma (GBM). V-domain immunoglobulin suppressor of T-cell activation (VISTA) is significantly up-regulated in GBM patients; however, its therapeutic potential in GBM is still unclear.
Flow cytometry was used to detect the expression of VISTA and the co-expression pattern of VISTA and programmed death receptor 1 (PD-1) on brain infiltrating lymphocytes of GBM mice. Monoclonal antibody therapy was used to evaluate the therapeutic effect of α-VISTA monotherapy and α-VISTA combined with α-PD-1 on GBM mice. Transcriptome analysis, flow cytometry, and immunofluorescence were used to detect changes of immune microenvironment in mouse brain tumours. Immunofluorescence and TCGA data analysis were used to further validate the combined treatment strategy on patient data.
Compared with normal mice, the frequency of VISTA expression and co-expression of VISTA and PD-1 on tumour-infiltrating lymphocytes (TILs) in tumour-bearing mice was increased. Anti-VISTA monotherapy significantly up-regulated multiple immune stimulation-related pathways and moderately prolonged mouse survival time. Blocking the immune checkpoint VISTA and PD-1 significantly prolonged the survival time of mice and cured about 80% of the mice; CD8 T cells played an important role in this process. In addition, we found that the expression of VISTA and PD-1 was significantly up-regulated in GBM patients by immunofluorescence, and patients with high expression of VISTA and PD-1 were associated with poor overall survival. This combination of blocking the immune checkpoint VISTA and PD-1 may achieve clinical transformation in GBM.
目前的治疗方法无法满足胶质母细胞瘤（GBM）的治疗需求。T细胞活化V结构域免疫球蛋白抑制因子（VISTA）在GBM患者中显著上调；然而，其在GBM中的治疗潜力仍不清楚。
采用流式细胞术检测VISTA在GBM小鼠脑浸润淋巴细胞上的表达以及VISTA与程序性死亡受体1（PD-1）的共表达模式。采用单克隆抗体疗法评估α-VISTA单药治疗以及α-VISTA联合α-PD-1对GBM小鼠的治疗效果。运用转录组分析、流式细胞术和免疫荧光检测小鼠脑肿瘤免疫微环境的变化。采用免疫荧光和TCGA数据分析进一步验证患者数据的联合治疗策略。
与正常小鼠相比，荷瘤小鼠肿瘤浸润淋巴细胞（TILs）上VISTA的表达频率以及VISTA与PD-1的共表达频率增加。抗VISTA单药治疗显著上调多个免疫刺激相关通路，并适度延长小鼠存活时间。阻断免疫检查点VISTA和PD-1可显著延长小鼠存活时间，并使约80%的小鼠治愈；CD8 T细胞在此过程中发挥重要作用。此外，我们通过免疫荧光发现GBM患者中VISTA和PD-1的表达显著上调，VISTA和PD-1高表达的患者总生存期较差。这种阻断免疫检查点VISTA和PD-1的联合治疗可能在GBM中实现临床转化。
