4.6 Article

RAGE ablation attenuates glioma progression and enhances tumor immune responses by suppressing galectin-3 expression

Journal

NEURO-ONCOLOGY
Volume 25, Issue 5, Pages 886-898

Publisher

OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/noac250

Keywords

brain tumor; glioblastoma; macrophage; microglia

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Through genetic ablation of RAGE in two murine glioma models, we found that intracellular RAGE ablation suppresses tumor growth and invasion by suppressing AKT and ERK1/2 activities and downregulating MMP9 expression. In addition, RAGE inhibition enhances tumor inflammatory responses and potentiates the efficacy of immune checkpoint blockade therapy.
Background Malignant gliomas consist of heterogeneous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment. Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth and invasion. However, treatment strategies that only target the interaction of RAGE with its ligands are ineffective as cancer therapies due to the abundance and diversity of exogenous RAGE ligands in gliomas. Methods As an alternative approach to RAGE ligand inhibition, we evaluated the genetic ablation of RAGE on the tumorigenicity of 2 syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by histology, survival, Nanostring, and flow cytometry. Results Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition in both glioma models enhanced tumor inflammatory responses by downregulating the expression of galectin-3 and potentiated immunotherapy responses to immune checkpoint blockade. Conclusions We demonstrated that intracellular RAGE ablation suppresses multiple cellular pathways that are important in glioma progression, invasion, and immune escape. These findings strongly support the development of RAGE ablation as a treatment strategy for malignant gliomas.

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