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

Geraldo, Luiz Henrique Medeiros; Xu, Yunling; Jacob, Laurent; Pibouin-Fragner, Laurence; Rao, Rohit; Maïssa, Nawal; Verreault, Maïté; Lemaire, Nolwenn; Knosp, Camille; Lesaffre, Corinne; Daubon, Thomas; Dejaegher, Joost; Solie, Lien; Rudewicz, Justine; Viel, Thomas; Tavitian, Bertrand; Vleeschouwer, Steven De; Sanson, Marc; Bikfalvi, Andréas; Idbaïh, Ahmed; Lu, Qi; Lima, Flávia Regina Souza; Thomas, Jean‐Léon; Eichmann, Anne; Mathivet, Thomas

doi:10.1172/jci141083

Cited by 64 publications

(65 citation statements)

References 91 publications

(78 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…90 min after spinal intrathecal injection of OVA-A 488 , mice were anesthetized with ketamine/xylazine. LNs (mandibular, accessory mandibular, deep cervical, sciatic, and lumbar) were dissected and processed as previously described ( Geraldo et al, 2021 ). LNs were digested with DMEM containing 2.5 mg/ml collagenase D and 5 U/ml DNase I for 20 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Conserved meningeal lymphatic drainage circuits in mice and humans

Jacob

Neto

Lenck

et al. 2022

Journal of Experimental Medicine

Self Cite

View full text Add to dashboard Cite

Meningeal lymphatic vessels (MLVs) were identified in the dorsal and caudobasal regions of the dura mater, where they ensure waste product elimination and immune surveillance of brain tissues. Whether MLVs exist in the anterior part of the murine and human skull and how they connect with the glymphatic system and extracranial lymphatics remained unclear. Here, we used light-sheet fluorescence microscopy (LSFM) imaging of mouse whole-head preparations after OVA-A555 tracer injection into the cerebrospinal fluid (CSF) and performed real-time vessel-wall (VW) magnetic resonance imaging (VW-MRI) after systemic injection of gadobutrol in patients with neurological pathologies. We observed a conserved three-dimensional anatomy of MLVs in mice and humans that aligned with dural venous sinuses but not with nasal CSF outflow, and we discovered an extended anterior MLV network around the cavernous sinus, with exit routes through the foramina of emissary veins. VW-MRI may provide a diagnostic tool for patients with CSF drainage defects and neurological diseases.

show abstract

Section: Methodsmentioning

confidence: 99%

Conserved meningeal lymphatic drainage circuits in mice and humans

Jacob

Neto

Lenck

et al. 2022

Journal of Experimental Medicine

Self Cite

View full text Add to dashboard Cite

show abstract

“…SLIT2 is an immune-related gene that regulates cell growth and migration ( 24 ). It can recruit immune cells, such as macrophages ( 33 , 34 ). However, the mechanism may be different in the liver.…”

Section: Discussionmentioning

confidence: 99%

Identification of Liver Immune Microenvironment-Related Hub Genes in Liver of Biliary Atresia

et al. 2022

View full text Add to dashboard Cite

Background: Biliary atresia (BA) is one of the most common and fatal abnormalities of newborns. Increasing evidences indicated that immunology was the critical part of the etiology. This research used a public gene expression database to explore the immune microenvironment of BA liver.Methods: The gene expression profiles GSE46960, GSE159720, and GSE15235, containing BA and normal liver gene expression data, were obtained from the Expression Omnibus Gene. We applied CIBERSORTx to quantify 22 subsets of immune cells in BA liver. The differentially expressed genes (DEGs) and immune cells were used to further explore their relationship with liver fibrosis and the inflammation status of BA.Results: The expression of immune-related genes CXCL6, CXCL8, CXCL10, CCL20, IL32, TGFB2, SPP1, and SLIT2 was significantly different between BA and normal liver, among which CXCL8 was the hub gene. Six of 22 immune cell proportions were significantly different between BA and normal liver. Specifically, M0 macrophages and resting memory CD4+ T cells were upregulated in BA liver compared with normal liver. Meanwhile, monocytes, resting natural killer (NK) cells, plasma cells, and regulatory T (Treg) cells were downregulated. A further correlation analysis revealed that SLIT2 and CXCL6 owned high positive correlation coefficients with fibrosis grade, while the proportion of resting NK cells was negatively correlated. Proportions of resting CD4+ memory T cells were strongly related to the inflammation grade of BA liver.Conclusion: Biliary atresia is a disease strongly correlated with immune response. Our results might provide a clue for further exploration of BA etiology, which may promote a potential prediction model based on immune infiltration features.

show abstract

“…Similarly, miR-21 maturation in GAM-secreted exosomes can increase the secretion of M2-type cytokines IL6 and TGF-βI, thereby promoting the M2-type polarization of GAMs and increasing the resistance of GBM cells to the TMZ treatment ( 94 ). Furthermore, SLIT2-induced macrophage invasion and M2-type polarization in mouse GBM cells and human patient-derived GBM xenografts have exhibited enhancement of the therapeutic resistance of GBM to chemo- and immunotherapies ( 95 ). In the anti-angiogenic therapy of GBM, the recruitment and M2-type polarization of BMDMs following the administration of VEGF inhibitors constitute an immunosuppressive microenvironment, leading to treatment resistance ( 96 ).…”

Section: Gam Cells’ Role In Glioma Progression and Treatment Resistancementioning

confidence: 99%

“…Integrin αvβ5 acts as the major receptor for OPN ( 100 ). Similarly, mucin (MUC1) and polypeptide SLIT2 have also been shown to be involved in the M2-type polarization of GAMs ( 95 , 101 ). Moreover, GBM cells activate CD74 expression and induce the transformation of GAMs from M1- to M2-type polarization by secreting MIFs ( 70 ).…”

Section: Regulators Of M1/m2-gam Activation and Transformationmentioning

confidence: 99%

Origin, activation, and targeted therapy of glioma-associated macrophages

Cheng

Xiao²,

Li³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

The glioma tumor microenvironment plays a crucial role in the development, occurrence, and treatment of gliomas. Glioma-associated macrophages (GAMs) are the most widely infiltrated immune cells in the tumor microenvironment (TME) and one of the major cell populations that exert immune functions. GAMs typically originate from two cell types-brain-resident microglia (BRM) and bone marrow-derived monocytes (BMDM), depending on a variety of cytokines for recruitment and activation. GAMs mainly contain two functionally and morphologically distinct activation types- classically activated M1 macrophages (antitumor/immunostimulatory) and alternatively activated M2 macrophages (protumor/immunosuppressive). GAMs have been shown to affect multiple biological functions of gliomas, including promoting tumor growth and invasion, angiogenesis, energy metabolism, and treatment resistance. Both M1 and M2 macrophages are highly plastic and can polarize or interconvert under various malignant conditions. As the relationship between GAMs and gliomas has become more apparent, GAMs have long been one of the promising targets for glioma therapy, and many studies have demonstrated the therapeutic potential of this target. Here, we review the origin and activation of GAMs in gliomas, how they regulate tumor development and response to therapies, and current glioma therapeutic strategies targeting GAMs.

show abstract

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

Cited by 64 publications

References 91 publications

Conserved meningeal lymphatic drainage circuits in mice and humans

Conserved meningeal lymphatic drainage circuits in mice and humans

Identification of Liver Immune Microenvironment-Related Hub Genes in Liver of Biliary Atresia

Origin, activation, and targeted therapy of glioma-associated macrophages

Contact Info

Product

Resources

About