Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.
Biomedical Sciences Institute, Federal University of Rio de Janeiro, Brazil.
J Clin Invest. 2021 Aug 16;131(16). doi: 10.1172/JCI141083.
SLIT2 is a secreted polypeptide that guides migration of cells expressing Roundabout 1 and 2 (ROBO1 and ROBO2) receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient-derived GBM xenografts reduced tumor growth and rendered tumors sensitive to immunotherapy. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1- and ROBO2-mediated PI3K-γ activation. Macrophage Robo1 and Robo2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a potentially novel regulator of the GBM microenvironment and immunotherapeutic target for brain tumors.
SLIT2 是一种分泌性多肽，可指导表达 Roundabout 1 和 2（ROBO1 和 ROBO2）受体的细胞迁移。在此，我们研究了 SLIT2/ROBO 信号在神经胶质瘤中的作用。在患有胶质母细胞瘤（GBM）的患者中，SLIT2 的表达随着恶性进展而增加，与不良预后和免疫抑制相关。在小鼠神经胶质瘤细胞和患者来源的 GBM 异种移植物中敲低 SLIT2 可减少肿瘤生长，并使肿瘤对免疫疗法敏感。肿瘤细胞 SLIT2 敲低抑制了巨噬细胞浸润，并促进了细胞毒性基因表达谱，改善了肿瘤血管功能，并增强了化疗和免疫疗法的疗效。从机制上讲，SLIT2 通过 ROBO1 和 ROBO2 介导的 PI3K-γ 激活促进了小胶质细胞/巨噬细胞趋化性和肿瘤支持性极化。巨噬细胞 Robo1 和 Robo2 缺失和系统性 SLIT2 陷阱递送模拟了 SLIT2 敲低对肿瘤生长和肿瘤微环境（TME）的影响，揭示了通过巨噬细胞 ROBO 进行的 SLIT2 信号传导是 GBM 微环境的一个潜在新型调节剂，也是脑肿瘤的免疫治疗靶点。
