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SLIT2/ROBO signaling in tumor-associated microglia and macrophages drives glioblastoma immunosuppression and vascular dysmorphia.
Geraldo, Luiz H; Xu, Yunling; Jacob, Laurent; Pibouin-Fragner, Laurence; Rao, Rohit; Maissa, Nawal; Verreault, Maïté; Lemaire, Nolwenn; Knosp, Camille; Lesaffre, Corinne; Daubon, Thomas; Dejaegher, Joost; Solie, Lien; Rudewicz, Justine; Viel, Thomas; Tavitian, Bertrand; De Vleeschouwer, Steven; Sanson, Marc; Bikfalvi, Andreas; Idbaih, Ahmed; Lu, Q Richard; Lima, Flavia Rs; Thomas, Jean-Leon; Eichmann, Anne; Mathivet, Thomas.
Afiliação
  • Geraldo LH; Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.
  • Xu Y; Biomedical Sciences Institute, Federal University of Rio de Janeiro, Brazil.
  • Jacob L; Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.
  • Pibouin-Fragner L; Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.
  • Rao R; Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.
  • Maissa N; Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Verreault M; Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.
  • Lemaire N; Sorbonne Université, INSERM U1127, CNRS UMR 7225, Institut du Cerveau, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
  • Knosp C; Sorbonne Université, INSERM U1127, CNRS UMR 7225, Institut du Cerveau, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
  • Lesaffre C; Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.
  • Daubon T; Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.
  • Dejaegher J; INSERM U1029.
  • Solie L; Université de Bordeaux, Pessac, France.
  • Rudewicz J; Department of Neurosciences and.
  • Viel T; Department of Neurosurgery, UZ Leuven, Leuven, Belgium.
  • Tavitian B; Department of Neurosciences and.
  • De Vleeschouwer S; Department of Neurosurgery, UZ Leuven, Leuven, Belgium.
  • Sanson M; INSERM U1029.
  • Bikfalvi A; Université de Bordeaux, Pessac, France.
  • Idbaih A; Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.
  • Lu QR; Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.
  • Lima FR; Department of Neurosciences and.
  • Thomas JL; Department of Neurosurgery, UZ Leuven, Leuven, Belgium.
  • Eichmann A; Sorbonne Université, INSERM U1127, CNRS UMR 7225, Institut du Cerveau, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
  • Mathivet T; Onconeurotek Tumor Bank, Institut du Cerveau et de la Moelle épinière-ICM, Paris, France.
J Clin Invest ; 131(16)2021 08 16.
Article em En | MEDLINE | ID: mdl-34181595
ABSTRACT
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Receptores Imunológicos / Glioblastoma / Peptídeos e Proteínas de Sinalização Intercelular / Proteínas do Tecido Nervoso Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Receptores Imunológicos / Glioblastoma / Peptídeos e Proteínas de Sinalização Intercelular / Proteínas do Tecido Nervoso Idioma: En Ano de publicação: 2021 Tipo de documento: Article