肿瘤细胞治疗研究
英文原题：Harnessing γδ T cells for B7-H3-targeting CAR therapy to enhance anti-tumor therapy in glioblastoma.
Harnessing γδ T cells for B7-H3-targeting CAR therapy to enhance anti-tumor therapy in glioblastoma.
因此，B7 H3 CAR-T 细胞代表了一种有前景的 GBM 免疫治疗新方法，通过持续的平台优化和临床探索，可能为胶质瘤患者带来新的治疗希望。
胶质母细胞瘤（GBM）在很大程度上仍无法治愈，部分原因是高度免疫抑制的肿瘤微环境（TME）对包括嵌合抗原受体（CAR）-T细胞疗法在内的常规疗法构成了主要障碍。与常规T细胞相比，T细胞连接了固有免疫和适应性免疫，通过细胞因子分泌以及与其他免疫细胞群体的交互作用放大抗肿瘤反应，因此用靶向B7 H3的CAR武装T细胞，可将它们固有的肿瘤归巢和免疫调节能力与精准的抗原特异性细胞毒性结合起来，从而产生治疗协同效应。
利用TCGA和CGGA队列的Bulk RNA-seq和单细胞RNA-seq数据，分析了CD276（B7 H3）的表达及其预后相关性。从健康供体外周血单个核细胞中扩增人T细胞和常规T细胞，并用第二代B7 H3 CAR进行工程化改造。通过流式细胞术评估CAR表达和表型。使用细胞毒性和细胞因子释放试验评估对B7 H3+胶质瘤细胞系（U87、U251）的抗肿瘤活性。在携带胶质瘤异种移植瘤的NSG小鼠中测试治疗效果，通过免疫荧光评估肿瘤生长、生存、肿瘤浸润、凋亡和检查点表达。
B7 H3 CAR-T 细胞在 GBM 模型中表现出优于 B7 H3 CAR-T 细胞的抗肿瘤功能。体外实验中，B7 H3 CAR-T 细胞对 GBM 细胞系显示出增强且持久的细胞毒性，并分泌显著更高水平的关键效应细胞因子（IFN-、TNF-），提示其具有多功能且抗耗竭的表型。在 GBM 小鼠模型中，单次剂量的 B7 H3 CAR-T 细胞介导了强效的肿瘤控制并显著延长了生存期。机制研究将这一更优疗效追溯至增强的肿瘤浸润以及对肿瘤细胞凋亡更强效的诱导。
BACKGROUND: Glioblastoma (GBM) remains largely incurable, in part because the highly immunosuppressive tumor microenvironment (TME) poses a major barrier to conventional therapies, including to chimeric antigen receptor (CAR)-T cell therapy. Compared with conventional T cells, T cells bridge innate and adaptive immunity, amplifying anti-tumor responses through cytokine secretion and cross-talk with other immune populations, so arming T cells with a B7 H3-targeting CAR could combine their inherent tumor-homing and immunomodulatory capabilities with precise antigen-specific cytotoxicity for therapeutic synergy. METHODS: CD276 (B7 H3) expression and prognostic relevance were analyzed using bulk and single-cell RNA-seq data from TCGA and CGGA cohorts. Human T cells and conventional T cells were expanded from healthy donor PBMCs and engineered with a second-generation B7 H3 CAR. CAR expression and phenotype were assessed by flow cytometry. Antitumor activity against B7 H3+ glioma cell lines (U87, U251) was evaluated using cytotoxicity and cytokine-release assays. Therapeutic efficacy was tested in NSG mice bearing glioma xenografts, with tumor growth, survival, tumor infiltration, apoptosis, and checkpoint expression assessed by immunofluorescence. RESULTS: B7 H3 CAR- T cells exhibited superior antitumor functionality compared with B7 H3 CAR- T cells in GBM models. In vitro, B7 H3 CAR- T cells displayed enhanced, sustained cytotoxicity against GBM cell lines and secreted significantly higher levels of key effector cytokines (IFN- , TNF- ) than B7 H3 CAR- T cells, indicating a polyfunctional and exhaustion-resistant phenotype. In GBM mouse models, a single dose of B7 H3 CAR- T cells mediated robust tumor control and significantly prolonged survival. Mechanistic studies traced this superior efficacy to enhanced tumor infiltration and more potent induction of tumor cell apoptosis. CONCLUSIONS: B7 H3 CAR- T cells therefore represent a promising new approach to GBM immunotherapy which, through ongoing platform optimization and clinical exploration, could offer new therapeutic hope to patients with glioma.
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