SLIT2/ROBO signaling in tumor-associated microglia and macrophages drives glioblastoma immunosuppression and vascular dysmorphia
Copyright policy )SLIT2/ROBO signaling in tumor-associated microglia and macrophages drives glioblastoma immunosuppression and vascular dysmorphia
AbstractSLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM),SLIT2expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown ofSLIT2in mouse glioma cells and patient derived GBM xenografts reduced tumor growth and synergized with immunotherapy to prolong survival. Tumor cellSLIT2knockdown 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&2-mediated PI3Kγ activation. MacrophageRobo1&2deletion and systemic SLIT2 trap delivery mimickedSLIT2knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a novel regulator of the GBM microenvironment and a potential immunotherapeutic target for brain tumors.
- Université de Paris France
- ICM Partners United States
- Sorbonne University France
- Inserm France
- University of Paris France
Research & Experimental Medicine, CELL-MIGRATION, Brain cancer, ANGIOGENESIS, ACTIVATION, Mice, Tumor Microenvironment, BRAIN, Receptors, Immunologic, MICROENVIRONMENTAL LANDSCAPE, 11 Medical and Health Sciences, Brain Neoplasms, ROBO1, Prognosis, CANCER, Gene Expression Regulation, Neoplastic, Medicine, Research & Experimental, Oncology, SLIT, Gene Knockdown Techniques, Disease Progression, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Heterografts, Intercellular Signaling Peptides and Proteins, Immunotherapy, Microglia, Life Sciences & Biomedicine, Signal Transduction, Roundabout Proteins, Immunology, Nerve Tissue Proteins, Slit Homolog 2 Protein, [SDV.CAN] Life Sciences [q-bio]/Cancer, Vascular Biology, E-CADHERIN, Immune Tolerance, Animals, Humans, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, NEUROPILIN 1, Science & Technology, 42 Health sciences, 31 Biological sciences, Macrophages, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, 32 Biomedical and clinical sciences, Mice, Inbred C57BL, Glioblastoma
Research & Experimental Medicine, CELL-MIGRATION, Brain cancer, ANGIOGENESIS, ACTIVATION, Mice, Tumor Microenvironment, BRAIN, Receptors, Immunologic, MICROENVIRONMENTAL LANDSCAPE, 11 Medical and Health Sciences, Brain Neoplasms, ROBO1, Prognosis, CANCER, Gene Expression Regulation, Neoplastic, Medicine, Research & Experimental, Oncology, SLIT, Gene Knockdown Techniques, Disease Progression, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Heterografts, Intercellular Signaling Peptides and Proteins, Immunotherapy, Microglia, Life Sciences & Biomedicine, Signal Transduction, Roundabout Proteins, Immunology, Nerve Tissue Proteins, Slit Homolog 2 Protein, [SDV.CAN] Life Sciences [q-bio]/Cancer, Vascular Biology, E-CADHERIN, Immune Tolerance, Animals, Humans, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, NEUROPILIN 1, Science & Technology, 42 Health sciences, 31 Biological sciences, Macrophages, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, 32 Biomedical and clinical sciences, Mice, Inbred C57BL, Glioblastoma
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