Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Sci Transl Med. 2023 Feb 15;15(683):eabq3558. doi: 10.1126/scitranslmed.abq3558.
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.
基于 T 细胞的免疫疗法有望治疗实体瘤，但由于肿瘤内免疫抑制，其治疗效果受到限制。这种免疫抑制的肿瘤微环境主要由肿瘤相关的髓系细胞驱动，包括巨噬细胞。在这里，我们报告了一种小分子化合物——川楝素（TSN），它可以重编程巨噬细胞，在小鼠模型中增强胶质母细胞瘤（GBM）的抗肿瘤免疫。我们用化学文库对经过基因探测的巨噬细胞进行功能筛选，发现 TSN 逆转了巨噬细胞介导的肿瘤免疫抑制，导致 T 细胞浸润、激活增加，耗竭减少。化学蛋白质组学和结构分析表明，TSN 与 Hck 和 Lyn 相互作用，从而消除抑制性巨噬细胞免疫。此外，免疫检查点阻断和 TSN 联合治疗可诱导小鼠同源性 GBM 肿瘤消退。此外，TSN 治疗使 GBM 对表皮生长因子受体变异体 8 嵌合抗原受体（CAR）T 细胞治疗敏感。这些发现表明，TSN 可能是一种治疗化合物，可阻断肿瘤免疫抑制，并规避 GBM 及其他实体瘤中 T 细胞免疫治疗的肿瘤耐药性，值得进一步研究。
