Vordermark Kira, Pu JingJing, Sharma Amit, Maciacyzk Jarek, Schmidt-Wolf Ingo G H
Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital of Bonn, Bonn, Germany.
Department of Stereotactic and Functional Neurosurgery, University Hospital of Bonn, Bonn, Germany.
Cancer Med. 2024 Dec;13(24):e70497. doi: 10.1002/cam4.70497.
Cytokine-induced killer (CIK) cell therapy has proven successful in clinical trials regarding glioblastoma. Equally important are the hints suggesting peroxisome proliferator-activated receptors (PPARs) ligands being co-expressed in the central nervous system (CNS). This provides a rationale about investigating the possible synergistic effect of CIK cells and PPARs.
We investigated neuroblastoma and glioblastoma cell lines with mature CIK cells and the PPARγ antagonist GW-9662 to assess the effects on cell viability, candidate gene expression (Wnt/β-catenin signalling, DNMT1) and global methylation levels (5-methylcytosine, LINE-1).
Using a clinical applicable PPAR-γ inhibitor, we showed that (1) PPARγ-antagonist GW-9662 suppressed tumor cell growth in both neuroblastoma and glioblastoma cells, (2) PPARγ inhibition had restricted effect on the expression of Wnt/β-catenin associated genes, (3) inhibition of PPARγ led to downregulation of DNMT1 expression, supporting their hypothesized interaction in cancer, (4) a partial modulation of global LINE-1 methylation levels was observed, indicating their role in epigenetic processes, and (5) Combining PPARγ inhibition with CIK cell immunotherapy enhanced cell lysis significantly.
We provide evidence that PPAR ligands in combination with CIK cell immunotherapy could be a valuable option for malignant CNS tumors.
细胞因子诱导的杀伤细胞（CIK）疗法在胶质母细胞瘤的临床试验中已被证明是成功的。同样重要的是，有迹象表明过氧化物酶体增殖物激活受体（PPARs）配体在中枢神经系统（CNS）中共同表达。这为研究CIK细胞与PPARs可能的协同作用提供了理论依据。
我们用成熟的CIK细胞和PPARγ拮抗剂GW-9662研究神经母细胞瘤和胶质母细胞瘤细胞系，以评估对细胞活力、候选基因表达（Wnt/β-连环蛋白信号通路、DNMT1）和整体甲基化水平（5-甲基胞嘧啶、LINE-1）的影响。
使用临床适用的PPAR-γ抑制剂，我们发现：（1）PPARγ拮抗剂GW-9662抑制神经母细胞瘤和胶质母细胞瘤细胞中的肿瘤细胞生长；（2）PPARγ抑制对Wnt/β-连环蛋白相关基因的表达影响有限；（3）PPARγ抑制导致DNMT1表达下调，支持它们在癌症中假设的相互作用；（4）观察到整体LINE-1甲基化水平有部分调节，表明它们在表观遗传过程中的作用；（5）将PPARγ抑制与CIK细胞免疫疗法相结合可显著增强细胞裂解。
我们提供的证据表明，PPAR配体与CIK细胞免疫疗法联合应用可能是恶性中枢神经系统肿瘤的一种有价值的选择。
