SLIT2/ROBO signaling in tumor-associated microglia and macrophages drives glioblastoma immunosuppression and vascular dysmorphia

  • J Clin Invest. 2021 Aug 16;131(16):e141083. doi: 10.1172/JCI141083.
Luiz H Geraldo  1  2 ,  Yunling Xu  1 ,  Laurent Jacob  1 ,  Laurence Pibouin-Fragner  1 ,  Rohit Rao  3 ,  Nawal Maissa  1 ,  Maïté Verreault  4 ,  Nolwenn Lemaire  4 ,  Camille Knosp  1 ,  Corinne Lesaffre  1 ,  Thomas Daubon  5  6 ,  Joost Dejaegher  7  8 ,  Lien Solie  7  8 ,  Justine Rudewicz  5  6 ,  Thomas Viel  1 ,  Bertrand Tavitian  1 ,  Steven De Vleeschouwer  7  8 ,  Marc Sanson  4  9 ,  Andreas Bikfalvi  5  6 ,  Ahmed Idbaih  4 ,  Q Richard Lu  3 ,  Flavia Rs Lima  2 ,  Jean-Leon Thomas  4  10 ,  Anne Eichmann  1  11  12 ,  Thomas Mathivet  1
Affiliations
  • 1. Université de Paris, Paris Cardiovascular Research Center, INSERM, Paris, France.
  • 2. Biomedical Sciences Institute, Federal University of Rio de Janeiro, Brazil.
  • 3. Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • 4. 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.
  • 5. INSERM U1029.
  • 6. Université de Bordeaux, Pessac, France.
  • 7. Department of Neurosciences and.
  • 8. Department of Neurosurgery, UZ Leuven, Leuven, Belgium.
  • 9. Onconeurotek Tumor Bank, Institut du Cerveau et de la Moelle épinière-ICM, Paris, France.
  • 10. Department of Neurology.
  • 11. Cardiovascular Research Center, Department of Internal Medicine, and.
  • 12. Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.
PMID: 34181595 DOI: 10.1172/JCI141083
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.

Keywords
Brain cancer; Immunotherapy; Macrophages; Oncology; Vascular Biology.