Blocking PD1/PDL1 Interactions Together with MLN4924 Therapy is a Potential Strategy for Glioma Treatment.
Blocking PD1/PDL1 Interactions Together with MLN4924 Therapy is a Potential Strategy for Glioma Treatment.
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DOI：
10.4172/1948-5956.1000543
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Pereboeva L
中科院分区：
文献类型：
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作者：
Filippova N;Yang X;An Z;Nabors LB;Pereboeva L
MLN4924 是 cullin neddylation 的药理学抑制剂，可导致神经胶质瘤细胞凋亡、DNA 合成 S 期失调，因此为治疗脑肿瘤提供了巨大的潜力。然而，用 MLN4924 治疗靶向 neddylation 通路可以稳定缺氧诱导因子 1A (HIF1A)，它是癌细胞中免疫检查点分子 PDL1（程序死亡配体-1）的主要转录增强子之一。最近发现了免疫检查点分子对神经胶质瘤进展的影响；胶质瘤中 PDL1 过度表达会导致患者生存期显着缩短和抗肿瘤免疫反应降低。我们假设 i) MLN4924 治疗后神经胶质瘤中 PDL1 上调并诱导 T 细胞能量； ii) PD1/PDL1 阻断与 MLN4924 疗法的共同利用可能会降低 T 细胞能量，并可能使 MLN4924 诱导的肿瘤破坏与免疫反应相结合。利用免疫组织化学、分子生物学和生物化学方法评估神经胶质瘤、神经胶质瘤微环境和 MLN4924 治疗后的 PDL1 表达及其免疫抑制作用。我们确认了临床脑肿瘤样本、PDGx 和已建立的神经胶质瘤细胞系、神经胶质瘤细胞的细胞外介质以及荷瘤小鼠的脑脊液样本中 PDL1 过表达。我们基于 T 细胞的主要检测证实，肿瘤细胞中 PDL1 的上调可保护神经胶质瘤免受 T 细胞治疗并减少 T 细胞活化。我们发现 cullin neddylation 的药理学抑制剂 MLN4924 对 PDGx 表现出强烈的细胞毒性，并在体外建立了神经胶质瘤细胞系，IC50 范围为 0.2 至 3 uM。然而，我们观察到用 MLN4924 处理后，所有神经胶质瘤细胞系中 HIF1A 和 PDL1 的 mRNA 和蛋白质水平显着增加。神经胶质瘤中 MLN4924 依赖性的 PDL1 诱导产生 T 细胞能量，但这种能量会因 PD1/PDL1 相互作用的阻断而被阻断。我们的结论是：i) 神经胶质瘤和神经胶质瘤微环境中 PDL1 的上调是重要的化疗靶点； ii) MLN4924 疗法与 PD1/PDL1 通路阻断相结合，应被视为神经胶质瘤治疗的潜在策略。
MLN4924, a pharmacological inhibitor of cullin neddylation, resulted in glioma cell apoptosis, deregulation of the S-phase of DNA synthesis and thus, offers great potential for the treatment of brain tumours. However, targeting the neddylation pathway with an MLN4924 treatment stabilized the hypoxia-inducible factor 1A (HIF1A), which is one of the main transcriptional enhancers of the immune checkpoint molecule PDL1 (programmid death ligand-1) in cancer cells. The influence of immune checkpoint molecules on glioma progression has recently been discovered; PDL1 overexpression in gliomas corresponds to a significant shortening of patient survival and a decrease of the anti-tumour immune response. We hypothesize that i) PDL1 is up-regulated in gliomas after treatment with MLN4924 and induces T-cell energy; ii) co-utilization of the PD1/PDL1 blockage with MLN4924 therapy may reduce T-cell energy and may engage MLN4924-induced tumour disruption with the immune response. PDL1 expression and its immunosuppressive role in gliomas, glioma microenvironments, and after treatments with MLN4924 were assessed by utilizing methods of immunohistochemistry, molecular biology, and biochemistry. We confirmed PDL1 overexpression in clinical brain tumour samples, PDGx and established glioma cell lines, extracellular media from glioma cells, and CSF (cerebrospinal fluid) samples from tumour-bearing mice. Our primary T-cell based assays verified that the up-regulation of PDL1 in tumour cells protects gliomas from T-cell treatment and reduces T-cell activation. We found that a pharmacological inhibitor of cullin neddylation, MLN4924, exhibited strong cytotoxicity towards PDGx and established glioma cell lines, in vitro, with an IC50’s range from 0.2 to 3 uM. However, we observed a significant increase of HIF1A and PDL1 in mRNA and protein levels in all glioma cell lines after treatment with MLN4924. The MLN4924-dependent induction of PDL1 in gliomas resulted in T-cell energy, which was blocked by a blockage of the PD1/PDL1 interaction. We conclude that i) PDL1 up-regulation in gliomas and the glioma microenvironment is an important chemotherapeutic target; ii) MLN4924 therapy, combined with a blockage of the PD1/PDL1 pathway, should be considered as a potential strategy for glioma treatment.