Beijing Advanced Innovation Center for Biomedical Engineering, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing, 100191, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
J Transl Med. 2023 Sep 28;21(1):672. doi: 10.1186/s12967-023-04514-8.
Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. This study investigates the therapeutic potential of human Vγ9Vδ2 T cells in GBM treatment. The sensitivity of different glioma specimens to Vγ9Vδ2 T cell-mediated cytotoxicity is assessed using a patient-derived tumor cell clusters (PTCs) model.
The study evaluates the anti-tumor effect of Vγ9Vδ2 T cells in 26 glioma cases through the PTCs model. Protein expression of BTN2A1 and BTN3A1, along with gene expression related to lipid metabolism and glioma inflammatory response pathways, is analyzed in matched tumor tissue samples. Additionally, the study explores two strategies to re-sensitize tumors in the weak anti-tumor effect (WAT) group: utilizing a BTN3A1 agonistic antibody or employing bisphosphonates to inhibit farnesyl diphosphate synthase (FPPS). Furthermore, the study investigates the efficacy of genetically engineered Vγ9Vδ2 T cells expressing Car-B7H3 in targeting diverse GBM specimens.
The results demonstrate that Vγ9Vδ2 T cells display a stronger anti-tumor effect (SAT) in six glioma cases, while showing a weaker effect (WAT) in twenty cases. The SAT group exhibits elevated protein expression of BTN2A1 and BTN3A1, accompanied by differential gene expression related to lipid metabolism and glioma inflammatory response pathways. Importantly, the study reveals that the WAT group GBM can enhance Vγ9Vδ2 T cell-mediated killing sensitivity by incorporating either a BTN3A1 agonistic antibody or bisphosphonates. Both approaches support TCR-BTN mediated tumor recognition, which is distinct from the conventional MHC-peptide recognition by αβ T cells. Furthermore, the study explores an alternative strategy by genetically engineering Vγ9Vδ2 T cells with Car-B7H3, and both non-engineered and Car-B7H3 Vγ9Vδ2 T cells demonstrate promising efficacy in vivo, underscoring the versatile potential of Vγ9Vδ2 T cells for GBM treatment.
Vγ9Vδ2 T cells demonstrate a robust anti-tumor effect in some glioma cases, while weaker in others. Elevated BTN2A1 and BTN3A1 expression correlates with improved response. WAT group tumors can be sensitized using a BTN3A1 agonistic antibody or bisphosphonates. Genetically engineered Vγ9Vδ2 T cells, i.e., Car-B7H3, show promising efficacy. These results together highlight the versatility of Vγ9Vδ2 T cells for GBM treatment.
胶质母细胞瘤（GBM）是一种预后不良的高度侵袭性原发性脑肿瘤。本研究探讨了人 Vγ9Vδ2 T 细胞在 GBM 治疗中的治疗潜力。使用患者来源的肿瘤细胞簇（PTCs）模型评估不同神经胶质瘤标本对 Vγ9Vδ2 T 细胞介导的细胞毒性的敏感性。
本研究通过 PTCs 模型评估了 26 例神经胶质瘤病例中 Vγ9Vδ2 T 细胞的抗肿瘤作用。分析了匹配的肿瘤组织样本中 BTN2A1 和 BTN3A1 的蛋白表达，以及与脂质代谢和神经胶质瘤炎症反应途径相关的基因表达。此外，本研究还探讨了两种使弱抗肿瘤效果（WAT）组肿瘤重新敏感的策略：使用 BTN3A1 激动性抗体或使用双膦酸盐抑制法尼酰基辅酶 A 合酶（FPPS）。此外，本研究还研究了表达 Car-B7H3 的基因工程 Vγ9Vδ2 T 细胞靶向不同 GBM 标本的疗效。
结果表明，Vγ9Vδ2 T 细胞在 6 例神经胶质瘤病例中表现出更强的抗肿瘤作用（SAT），而在 20 例病例中表现出较弱的作用（WAT）。SAT 组 BTN2A1 和 BTN3A1 的蛋白表达升高，同时与脂质代谢和神经胶质瘤炎症反应途径相关的基因表达存在差异。重要的是，该研究揭示了 WAT 组 GBM 可以通过加入 BTN3A1 激动性抗体或双膦酸盐来增强 Vγ9Vδ2 T 细胞介导的杀伤敏感性。这两种方法都支持 TCR-BTN 介导的肿瘤识别，这与 αβ T 细胞的传统 MHC-肽识别不同。此外，本研究还探索了一种通过基因工程使 Vγ9Vδ2 T 细胞表达 Car-B7H3 的替代策略，非工程化和 Car-B7H3 Vγ9Vδ2 T 细胞在体内均显示出有希望的疗效，这突出了 Vγ9Vδ2 T 细胞在 GBM 治疗中的多功能潜力。
Vγ9Vδ2 T 细胞在一些神经胶质瘤病例中表现出强大的抗肿瘤作用，而在其他病例中作用较弱。BTN2A1 和 BTN3A1 的高表达与改善的反应相关。WAT 组肿瘤可以通过 BTN3A1 激动性抗体或双膦酸盐进行敏感化。基因工程 Vγ9Vδ2 T 细胞，即 Car-B7H3，显示出有希望的疗效。这些结果共同强调了 Vγ9Vδ2 T 细胞在 GBM 治疗中的多功能性。
