| Autor: |
Lien Solie, Maite Verreault, Q. R. Lu, S. De Vleeschouwer, Camille Knosp, Joost Dejaegher, N. Lemaire, Ahmed Idbaih, Bertrand Tavitian, Luiz H. Geraldo, Anne Eichmann, Thomas Viel, Thomas Daubon, Thomas Mathivet, Marc Sanson, Justine Rudewicz, Nawal Maïssa, Jean-Leon Thomas, Laurence Pibouin-Fragner, Flavia Regina Souza Lima, Laurent Jacob, Rohit Rao, Andreas Bikfalvi, Corinne Lesaffre, Y. Xu |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
SLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 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 synergized with immunotherapy to prolong survival. 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&2-mediated PI3Kγ activation. Macrophage Robo1&2 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 novel regulator of the GBM microenvironment and a potential immunotherapeutic target for brain tumors. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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