SLIT2/ROBO signaling in tumor-associated microglia and macrophages drives glioblastoma immunosuppression and vascular dysmorphia
Autor: | Joost Dejaegher, Anne Eichmann, Maite Verreault, Flavia Regina Souza Lima, Andreas Bikfalvi, Marc Sanson, Thomas Mathivet, Q. Richard Lu, Corinne Lesaffre, Yunling Xu, Luiz Henrique Medeiros Geraldo, Lien Solie, Ahmed Idbaih, Justine Rudewicz, Jean-Leon Thomas, Thomas Viel, Camille Knosp, Laurent Jacob, Rohit Rao, Bertrand Tavitian, Nolwenn Lemaire, Nawal Maïssa, Thomas Daubon, Steven De Vleeschouwer, Laurence Pibouin-Fragner |
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Přispěvatelé: | Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS) |
Rok vydání: | 2021 |
Předmět: |
[SDV]Life Sciences [q-bio]
medicine.medical_treatment Nerve Tissue Proteins Biology Brain cancer Macrophage chemotaxis Mice 03 medical and health sciences 0302 clinical medicine Vascular Biology Glioma Immune Tolerance Tumor Microenvironment medicine Animals Humans Macrophage Receptors Immunologic ComputingMilieux_MISCELLANEOUS PI3K/AKT/mTOR pathway 030304 developmental biology 0303 health sciences Tumor microenvironment Gene knockdown Microglia Brain Neoplasms Macrophages General Medicine Immunotherapy Prognosis medicine.disease 3. Good health Gene Expression Regulation Neoplastic Mice Inbred C57BL medicine.anatomical_structure Oncology Gene Knockdown Techniques 030220 oncology & carcinogenesis Disease Progression Cancer research Heterografts Intercellular Signaling Peptides and Proteins Glioblastoma Research Article Signal Transduction |
Zdroj: | J Clin Invest The Journal of clinical investigation The Journal of clinical investigation, 2021, 131 (16), ⟨10.1172/JCI141083⟩ |
ISSN: | 1558-8238 |
Popis: | 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. ispartof: JOURNAL OF CLINICAL INVESTIGATION vol:131 issue:16 ispartof: location:United States status: published |
Databáze: | OpenAIRE |
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