肿瘤细胞治疗研究
英文原题：Non-lytic viral immunotherapy induces long-term glioblastoma survival and tumor-specific immunity without eliciting an antiviral response.
胶质母细胞瘤是一种致命的脑肿瘤，对常规疗法具有耐药性。
胶质母细胞瘤是一种对常规疗法具有抵抗性的致死性脑肿瘤。在此，我们提出一种非裂解性复制型逆转录病毒（RRV），可将IL-15受体连接融合蛋白（RLI）超激动剂直接递送至胶质母细胞瘤细胞内，从而在局部构建免疫治疗生物工厂。在原位小鼠模型中，RRV-RLI显著抑制肿瘤生长、延长生存期，并诱导持久的缓解及免疫记忆。机制上，我们观察到CD8⁺ T细胞和NK 细胞浸润与活化增加，同时抗原呈递通路上调。将RRV-RLI与替莫唑胺（胶质母细胞瘤的标准治疗化疗药物）联合使用，可增强抗肿瘤免疫。T细胞受体测序显示T细胞呈多克隆谱系，且RRV-RLI与替莫唑胺联合可增强这一多克隆性。对T细胞库的分析提示其靶向肿瘤抗原而非病毒抗原，支持了该方法的特异性及可重复应用性。这些发现表明，RRV-RLI将胶质母细胞瘤重编程为免疫刺激枢纽，为胶质母细胞瘤及潜在的其他治疗抵抗性实体瘤提供了一种病毒免疫治疗策略。
Glioblastoma is a lethal brain tumor that is resistant to conventional therapies. Here we present a non-lytic replicating retrovirus (RRV) that delivers an IL-15-receptor-linked fusion protein (RLI) superagonist directly into glioblastoma cells, creating localized immunotherapy biofactories. In orthotopic mouse models, RRV-RLI dramatically suppresses tumor growth, prolongs survival, and induces lasting remission with immunologic memory. Mechanistically, we observe increased CD8⁺ T cell and natural killer cell infiltration and activation, alongside elevated antigen presentation pathways. Combining RRV-RLI with temozolomide, which is standard-of-care chemotherapy for glioblastoma, enhances antitumor immunity. T cell receptor sequencing reveals a polyclonal repertoire of T cells, enhanced by combining RRV-RLI with temozolomide. Analysis of the T-cell repertoire suggests it to be directed against tumor rather than viral antigens, supporting the specificity and re-applicability of our approach. These findings illustrate that RRV-RLI reprograms glioblastoma into an immunostimulatory hub, offering a viral immunotherapy against glioblastoma and potentially other therapy-resistant solid tumors.
MEMBER ACCOUNT
登录成功会直接打开下一页。
