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
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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