2. Academic Validation
  3. RAGE Ablation Attenuates Glioma Progression and Enhances Tumor Immune Responses by Suppressing Galectin-3 Expression

RAGE Ablation Attenuates Glioma Progression and Enhances Tumor Immune Responses by Suppressing Galectin-3 Expression

  • Neuro Oncol. 2022 Nov 17;noac250. doi: 10.1093/neuonc/noac250.
Ian Y Zhang 1,  Shunan Liu 2,  Leying Zhang 1,  Rongrui Liang 3,  Qinxiao Fang 4,  Jie Zhao 5,  Lyuzhi Ren 1,  Eric F Medina 6,  Aleksandr Filippov 6,  Kimberley-Jane Bonjoc 7,  Ammar Chaudhry 8,  Mojtaba Dayyani 1,  Andrea H Bild 9,  Behnam Badie 1
Affiliations

Affiliations

  • 1 Division of Neurosurgery, City of Hope Beckman Research Institute, Duarte, California, USA.
  • 2 Department of Pharmacology, The Pharmacy School of Jilin University, Changchun, Jilin Province, P.R. China.
  • 3 Department of Oncology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China.
  • 4 Colorectal Cancer Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
  • 5 Tianjin Union Medicine Center, Tianjin, 300123, P.R.China.
  • 6 Graduate Education Progr-BRI, City of Hope Beckman Research Institute, Duarte, California, USA.
  • 7 Imaging Administration, City of Hope Beckman Research Institute, Duarte, California, USA.
  • 8 Diagnostic Radiology, City of Hope Beckman Research Institute, Duarte, California, USA.
  • 9 Medical Oncology, City of Hope Beckman Research Institute, Duarte, California, USA.
PMID: 36394567 DOI: 10.1093/neuonc/noac250
Abstract

Background: Malignant gliomas consist of heterogenous 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 genetic ablation of RAGE on the tumorigenicity of two 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.

Keywords

Brain tumor; Glioblastoma; Macrophage; Microglia.

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