Small-molecule toosendanin reverses macrophage-mediated immunosuppression to overcome glioblastoma resistance to immunotherapy.
Small-molecule toosendanin reverses macrophage-mediated immunosuppression to overcome glioblastoma resistance to immunotherapy.
复制标题
小分子川楝素逆转巨噬细胞介导的免疫抑制，克服胶质母细胞瘤对免疫治疗的耐药性。
DOI：
10.1126/scitranslmed.abq3558
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发表时间：
2023
影响因子：
17.1
通讯作者：
Fan,Yi
中科院分区：
文献类型：
--
作者：
Yang,Fan;Zhang,Duo;Jiang,Haowen;Ye,Jiangbin;Zhang,Lin;Bagley,StephenJ;Winkler,Jeffery;Gong,Yanqing;Fan,Yi
基于T细胞的免疫疗法有望治疗实体瘤，但其治疗效果受到肿瘤内免疫抑制的限制。这种免疫抑制性肿瘤微环境主要由肿瘤相关的骨髓细胞（包括巨噬细胞）驱动。在这里，我们报告川楝素（TSN），一种小分子化合物，重新编程巨噬细胞，以加强小鼠模型胶质母细胞瘤（GBM）的抗肿瘤免疫。我们用化学文库对基因探测的巨噬细胞进行功能筛选，发现TSN逆转巨噬细胞介导的肿瘤免疫抑制，导致T细胞浸润增强、活化和耗竭减少。化学蛋白质组学和结构分析表明，TSN与Hck和林恩相互作用，消除抑制性巨噬细胞免疫。此外，免疫检查点阻断和TSN治疗的组合诱导小鼠中同基因GBM肿瘤的消退。此外，TSN处理使GBM对Egfrviii嵌合抗原受体（CAR）T细胞疗法敏感。这些发现表明，TSN可以作为一种治疗性化合物，阻断肿瘤免疫抑制，并避免肿瘤对GBM和其他实体瘤中基于T细胞的免疫治疗的耐药性，这需要进一步研究。
T cell–based immunotherapy holds promise for treating solid tumors, but its therapeutic efficacy is limited by intratumoral immune suppression. This immune suppressive tumor microenvironment is largely driven by tumor-associated myeloid cells, including macrophages. Here, we report that toosendanin (TSN), a small-molecule compound, reprograms macrophages to enforce antitumor immunity in glioblastoma (GBM) in mouse models. Our functional screen of genetically probed macrophages with a chemical library identifies that TSN reverses macrophage-mediated tumor immunosuppression, leading to enhanced T cell infiltration, activation, and reduced exhaustion. Chemoproteomic and structural analyses revealed that TSN interacts with Hck and Lyn to abrogate suppressive macrophage immunity. In addition, a combination of immune checkpoint blockade and TSN therapy induced regression of syngeneic GBM tumors in mice. Furthermore, TSN treatment sensitized GBM to Egfrviii chimeric antigen receptor (CAR) T cell therapy. These findings suggest that TSN may serve as a therapeutic compound that blocks tumor immunosuppression and circumvents tumor resistance to T cell–based immunotherapy in GBM and other solid tumors that warrants further investigation.