PDF(Pubmed)
Abstract：
Immunotherapies have shown significant promise as an impactful strategy in cancer treatment. However, in glioblastoma multiforme (GBM), the most prevalent primary brain tumor in adults, these therapies have demonstrated lower efficacy than initially anticipated. Consequently, there is an urgent need for strategies to enhance the effectiveness of immune treatments. AURKA has been identified as a potential drug target for GBM treatment. An analysis of the GBM cell transcriptome following AURKA inhibition revealed a potential influence on the immune system. Our research revealed that AURKA influenced PD-L1 levels in various GBM model systems in vitro and in vivo. Disrupting AURKA function genetically led to reduced PD-L1 levels and increased MHC-I expression in both established and patient-derived xenograft GBM cultures. This process involved both transcriptional and non-transcriptional pathways, partly implicating GSK3β. Interfering with AURKA also enhanced NK-cell-mediated elimination of GBM by reducing PD-L1 expression, as evidenced in rescue experiments. Furthermore, using a mouse model that mimics GBM with patient-derived cells demonstrated that Alisertib decreased PD-L1 expression in living organisms. Combination therapy involving anti-PD-1 treatment and Alisertib significantly prolonged overall survival compared to vehicle treatment. These findings suggest that targeting AURKA could have therapeutic implications for modulating the immune environment within GBM cells.
摘要：
免疫疗法已显示出作为癌症治疗中的有效策略的重要前景。然而,在多形性胶质母细胞瘤（GBM）中，成人中最常见的原发性脑肿瘤，这些疗法的疗效低于最初预期.因此,迫切需要提高免疫治疗效果的策略。AURKA已被确定为GBM治疗的潜在药物靶标。对AURKA抑制后的GBM细胞转录组的分析揭示了对免疫系统的潜在影响。我们的研究表明，AURKA在体外和体内影响了各种GBM模型系统中的PD-L1水平。遗传上破坏AURKA功能导致已建立和患者来源的异种移植物GBM培养物中PD-L1水平降低和MHC-I表达增加。这个过程涉及转录和非转录途径，部分涉及GSK3β。干扰AURKA还通过减少PD-L1表达来增强NK细胞介导的GBM消除，正如在救援实验中所证明的那样。此外，使用用患者来源的细胞模拟GBM的小鼠模型,证明了Alisertib降低了活生物体中PD-L1的表达.与媒介物治疗相比,涉及抗PD-1治疗和Alisertib的联合治疗显著延长了总生存期。这些发现表明靶向AURKA可能对调节GBM细胞内的免疫环境具有治疗意义。
