脊髓灰质炎病毒受体 (PVR) 与三种受体相互作用：T 细胞免疫球蛋白免疫受体酪氨酸抑制基序 (TIGIT)、CD96、DNAX 辅助分子 1 (DNAM)，这些受体主要在 T 细胞和自然杀伤细胞上表达。据报道，许多实体瘤，包括 IDH 野生型胶质母细胞瘤，过度表达 PVR，这种过度表达与不良预后相关。然而，尚无临床前或临床试验研究针对 IDH 野生型胶质母细胞瘤中 PVR 的细胞免疫疗法的使用。我们分析了转录组测序数据库和 IDH 野生型胶质母细胞瘤患者标本中的 PVR 表达。我们使用慢病毒开发了针对嵌合抗原受体（CAR）-T 细胞的 PVR。 CAR-T 细胞的抗肿瘤活性在患者来源的胶质瘤干细胞 (GSC)、颅内和皮下小鼠异种移植模型中得到证实。我们验证了原代 GSC、IDH 野生型胶质母细胞瘤患者的手术标本和类器官中的 PVR 表达。因此，我们开发了基于PVR受体的第二代CAR-T细胞。 CAR-T 细胞的抗肿瘤活性已在 GSC 和异种移植模型中得到证实。由于抗原丢失，颅内异种移植模型中出现肿瘤复发。基于TIGIT胞外域的CAR-T细胞和NK-92细胞的联合治疗显着抑制了肿瘤复发并延长了生存期。基于PVR受体的CAR-T细胞与NK-92细胞联合时能够杀死GSC并抑制肿瘤复发.© 作者 2023。由牛津大学出版社出版。

Poliovirus receptor (PVR) interacts with three receptors: T-cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif (TIGIT), CD96, DNAX accessory molecule-1 (DNAM), that are predominantly expressed on T cells and natural killer cells. Many solid tumors, including IDH-wildtype glioblastoma, have been reported to overexpress PVR, and this overexpression is associated with poor prognosis. However, there is no preclinical or clinical trials investigating the use of cell-based immunotherapies targeting PVR in IDH-wildtype glioblastoma.We analyzed PVR expression in transcriptome sequencing databases and specimens from IDH-wildtype glioblastoma patients. We developed PVR targeting chimeric antigen receptor (CAR)-T cells using lentivirus. The antitumor activity of CAR-T cells was demonstrated in patient-derived glioma stem cells (GSCs), intracranial and subcutaneous mouse xenograft models.We verified PVR expression in primary GSCs, surgical specimens from IDH-wildtype glioblastoma patients and organoids. Accordingly, we developed PVR receptor-based second-generation CAR-T cells. The antitumor activity of CAR-T cells was demonstrated in GSCs and xenograft models. Tumor recurrence occurred in intracranial xenograft model because of antigen loss. The combinational therapy of TIGIT extracellular domain-based CAR-T cells and NK-92 cells markedly suppressed tumor recurrence and prolonged survival.PVR receptor-based CAR-T cells were capable of killing GSCs and suppressing tumor recurrence when combined with NK-92 cells.© The Author(s) 2023. Published by Oxford University Press.