Therapeutic modulation of APP-CD74 axis can activate phagocytosis of TAMs in GBM

Area of Science:

• Neuro-oncology
• Cancer immunology
• Cellular signaling

Background:

• Glioblastoma multiforme (GBM) is a lethal brain cancer with limited treatment options.
• The tumor microenvironment, including tumor-associated macrophages (TAMs), significantly impacts GBM progression and patient outcomes.
• Understanding cell-cell communication within the GBM microenvironment is crucial for developing novel therapies.

Purpose of the Study:

• To investigate cell-cell communication networks within the GBM tumor microenvironment.
• To identify key signaling pathways mediating interactions between GBM cells and TAMs.
• To evaluate the therapeutic potential of targeting identified pathways in GBM.

Main Methods:

• Analysis of cell-cell communication in GBM patient samples.
• Assessment of amyloid precursor protein (APP) and CD74 expression levels.
• In vitro and in vivo experiments to evaluate the role of the APP-CD74 axis in TAM phagocytosis.
• Investigation of SHP-1 phosphorylation downstream of APP-CD74 signaling.

Main Results:

• High levels of cell communication were observed between GBM cells and TAMs.
• The amyloid precursor protein (APP)-CD74 axis showed the strongest communication between GBM cells and TAMs.
• APP expression on GBM cells inhibited TAM phagocytosis via the CD74/CXCR4 receptor complex.
• Disruption of the APP-CD74 axis enhanced TAM phagocytosis both in vitro and in vivo.
• APP binding to CD74 promoted SHP-1 phosphorylation.

Conclusions:

• The APP-CD74 axis represents a significant anti-phagocytic signaling pathway in GBM.
• Targeting the APP-CD74 axis could overcome immune evasion in GBM.
• This pathway presents a promising novel immunotherapeutic target for glioblastoma treatment.