文章：

替莫唑胺与PARP抑制剂尼拉帕利增强胶质母细胞瘤中自然杀伤细胞2D配体ULBP1的表达及γ-δ T细胞毒性

Temozolomide and the PARP Inhibitor Niraparib Enhance Expression of Natural Killer Group 2D Ligand ULBP1 and Gamma-Delta T Cell Cytotoxicity in Glioblastoma

原文发布日期：15 August 2024

DOI: 10.3390/cancers16162852

类型: Article

开放获取: 是

英文摘要：

Glioblastoma (GBM) is an immunologically cold tumor, but several immunotherapy-based strategies show promise, including the administration of ex vivo expanded and activated cytotoxic gamma delta T cells. Cytotoxicity is partially mediated through interactions with natural killer group 2D ligands (NKG2DL) on tumor cells. We sought to determine whether the addition of the blood–brain barrier penetrant PARP inhibitor niraparib to the standard of care DNA alkylator temozolomide (TMZ) could upregulate NKG2DL, thereby improving immune cell recognition. Changes in viability were consistent with prior publications as there was a growth inhibitory effect of the combination of TMZ and niraparib. However, decreases in viability did not always correlate with changes in NKG2DL mRNA.ULBP1/Mult-1mRNA was increased with the combination therapy in comparison to either drug alone in two of the three cell types tested, even though viability was consistently decreased. mRNA expression correlated with protein levels and ULBP1/MULT-1 cell surface protein was significantly increased with TMZ and niraparib treatment in four of the five cell types tested. Gamma delta T cell-mediated cytotoxicity at a 10:1 effector-to-target ratio was significantly increased upon pretreatment of cells derived from a GBM PDX with TMZ and niraparib in comparison to the control or either drug alone. Together, these data demonstrate that the combination of PARP inhibition, DNA alkylation, and gamma delta T cell therapy has the potential for the treatment of GBM.

摘要翻译： 

胶质母细胞瘤（GBM）是一种免疫学上的“冷”肿瘤，但多种基于免疫疗法的策略显示出潜力，包括使用体外扩增并活化的细胞毒性γδ T细胞。其细胞毒性部分通过肿瘤细胞表面的自然杀伤细胞2D配体（NKG2DL）相互作用介导。本研究旨在探讨在标准治疗药物DNA烷化剂替莫唑胺（TMZ）基础上，联合使用可穿透血脑屏障的PARP抑制剂尼拉帕利，能否上调NKG2DL表达，从而增强免疫细胞识别能力。细胞活力的变化与既往研究一致，TMZ与尼拉帕利联合应用表现出生长抑制作用。然而，细胞活力的降低并不总是与NKG2DL mRNA水平的变化相关。在测试的三种细胞类型中，有两种细胞的ULBP1/Mult-1 mRNA在联合治疗下较单药治疗显著升高，尽管细胞活力持续下降。mRNA表达与蛋白水平具有相关性，且在测试的五种细胞类型中，有四种细胞经TMZ和尼拉帕利处理后，其ULBP1/MULT-1细胞表面蛋白显著增加。以10:1的效应细胞与靶细胞比例进行实验时，相较于对照组或任一单药治疗，经TMZ和尼拉帕利预处理的GBM PDX来源细胞，其γδ T细胞介导的细胞毒性显著增强。综上所述，这些数据表明PARP抑制剂、DNA烷化剂与γδ T细胞疗法的联合应用具有治疗GBM的潜力。

原文链接：

Temozolomide and the PARP Inhibitor Niraparib Enhance Expression of Natural Killer Group 2D Ligand ULBP1 and Gamma-Delta T Cell Cytotoxicity in Glioblastoma