Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
SLIT2/ROBO signaling in tumor-associated microglia and macrophages drives glioblastoma immunosuppression and vascular dysmorphia
Luiz H. Geraldo, … , Anne Eichmann, Thomas Mathivet
Luiz H. Geraldo, … , Anne Eichmann, Thomas Mathivet
Published June 28, 2021
Citation Information: J Clin Invest. 2021;131(16):e141083. https://doi.org/10.1172/JCI141083.
View: Text | PDF
Research Article Oncology Vascular biology Article has an altmetric score of 11

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

  • Text
  • PDF
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.

Authors

Luiz H. Geraldo, Yunling Xu, Laurent Jacob, Laurence Pibouin-Fragner, Rohit Rao, Nawal Maissa, Maïté Verreault, Nolwenn Lemaire, Camille Knosp, Corinne Lesaffre, Thomas Daubon, Joost Dejaegher, Lien Solie, Justine Rudewicz, Thomas Viel, Bertrand Tavitian, Steven De Vleeschouwer, Marc Sanson, Andreas Bikfalvi, Ahmed Idbaih, Q. Richard Lu, Flavia R.S. Lima, Jean-Leon Thomas, Anne Eichmann, Thomas Mathivet

×

Figure 9

Robo1Fc treatment limits glioma growth.

Options: View larger image (or click on image) Download as PowerPoint
Robo1Fc treatment limits glioma growth.
(A) Eight-week-old mice engrafte...
(A) Eight-week-old mice engrafted with CT-2A spheroids were treated with CTRLFc or Robo1Fc as indicated, and analyzed at day 23. (B) ELISA of serum Slit2 (n = 4, 2-way ANOVA). (C and D) Tumor size at day 23 (n = 6, Student’s t test). (E–G) In vivo 2-photon images (E) and quantification of vessel diameter (F) and branchpoints (G) (n = 6 mice per group, 1-way ANOVA). (H) Quantification of Glut1+ area (n = 6 mice per group, Mann-Whitney U test). (I–K) Quantification of F4/80, MHC-II, and MRC1 (I), soluble-Flt1 binding (J), and CD3 immunostaining (K) (n = 6 mice per group, 2-way ANOVA (I) or Student’s t test). (L) Eight-week-old tumor-bearing mice were assigned to CTRLFc + vehicle (n = 20), CTRLFc + TMZ (n = 15), Robo1Fc + vehicle (n = 24), or Robo1Fc + TMZ (n = 22; OS 24 days CTRLFc; 28 days CTRLFc + TMZ; 41 days Robo1Fc; 119 days Robo1Fc + TMZ; multiple comparisons Mantel-Cox log-rank). (M) Eight-week-old tumor-bearing mice were assigned to CTRLFc + vehicle, CTRLFc + anti–PD-1 + anti–4-1BB, Robo1Fc + vehicle, or Robo1Fc + anti–PD-1 + anti–4-1BB (n = 10/11 mice per group; OS 25.5 days CTRLFc; 40 days CTRLFc + anti–PD-1 + anti–4-1BB; 39 days Robo1Fc; and undetermined for Robo1Fc + anti–PD-1 + anti–4-1BB; multiple comparisons log-rank test). (N) Ninety days after tumor implantation, surviving mice from M (n = 2 anti–PD-1 + anti–4-1BB, n = 3 Robo1Fc, and n = 8 Robo1Fc + anti–PD-1 + anti–4-1BB) or 8-week-old tumor-naive mice (n = 10) were rechallenged in the contralateral hemisphere (OS 21 days naive mice; 53.5 days CTRLFc + anti–PD-1 + anti–4-1BB survivors; 63 days Robo1Fc survivors; and undetermined for Robo1Fc + anti–PD-1 + anti–4-1BB survivors; multiple comparisons log-rank test). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 20 X users
65 readers on Mendeley
See more details