肿瘤细胞治疗研究
英文原题：Dasatinib boosts γδ T cell expansion and memory phenotypes with enhanced antitumor immunity.
这些结果提示达沙替尼可提高γδ T细胞的产量和功能，为优化基于γδ T细胞的过继治疗（尤其是实体瘤）提供了一种实用且可转化的策略。试验注册：试验编号：CMUH111-REC3-185。
γδ T 细胞因其不依赖 MHC 识别肿瘤抗原以及具有固有细胞毒性潜力，在肿瘤免疫治疗中具有独特优势。然而，使用唑来膦酸（Zol）和 IL-2 的传统体外扩增方案往往导致终末分化并削弱效应功能。在本研究中，我们基于流式细胞术对 FDA 批准的化合物库进行筛选，以鉴定能够在增强 γδ T 细胞扩增的同时保留其功能表型的药物。达沙替尼，一种临床使用的酪氨酸激酶抑制剂，成为一个有前景的治疗候选药物。经达沙替尼处理的 Vδ2 T 细胞（γδ2 T-Da）表现出扩增增加、记忆相关标志物（CD62L 和 CD127）表达升高、凋亡减少，以及 TNF-α 和 IFN-γ 产生增多。转录组分析显示与 T 细胞存活和自我更新相关的基因上调，包括 MYC、TCF7 和 MIR155HG。在功能上，γδ2 T-Da 细胞在体外对胶质母细胞瘤（GBM）和三阴性乳腺癌（TNBC）细胞表现出更强的细胞毒性，并且在长期培养后仍保持活性。在原位肿瘤模型中，γδ2 T-Da 细胞增强了肿瘤控制，减少了 TNBC 转移，并延长了 GBM 荷瘤小鼠的生存期。这些结果表明，达沙替尼可改善 γδ T 细胞的产量和功能，为优化基于 γδ T 细胞的过继治疗，尤其是针对实体瘤，提供了一种实用且可转化的策略。试验注册：试验编号：CMUH111-REC3-185。
Γδ T cells offer unique advantages in cancer immunotherapy because of their MHC-independent recognition of tumor antigens and innate cytotoxic potential. However, conventional ex vivo expansion protocols using zoledronic acid (Zol) and IL-2 often lead to terminal differentiation and diminished effector function. In this study, we performed a flow cytometry-based screen of an FDA-approved compound library to identify agents that enhance γδ T cell expansion while preserving their functional phenotypes. Dasatinib, a clinically used tyrosine kinase inhibitor, has emerged as a promising therapeutic candidate. Dasatinib-treated Vδ2 T cells (γδ2 T-Da) exhibited increased expansion, elevated expression of memory-associated markers (CD62L and CD127), reduced apoptosis, and higher production of TNF-α and IFN-γ. Transcriptomic analysis revealed the upregulation of genes related to T cell survival and self-renewal, including MYC, TCF7, and MIR155HG. Functionally, γδ2 T-Da cells demonstrated superior cytotoxicity against glioblastoma (GBM) and triple-negative breast cancer (TNBC) cells in vitro with sustained activity after prolonged culture. In orthotopic tumor models, γδ2 T-Da cells enhanced tumor control, reduced TNBC metastasis, and prolonged survival of GBM-bearing mice. These results suggest that dasatinib improves γδ T cell yield and function, providing a practical and translatable strategy for optimizing γδ T cell-based adoptive therapy, particularly for solid tumors.Trial registration: Trial number: CMUH111-REC3-185.
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