Granulocyte-Macrophage Colony Stimulating Factor Receptor Contributes to Plexiform Neurofibroma Initiation

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Plexiform neurofibroma (PNF) is a peripheral nerve sheath tumor common in Neurofibromatosis Type 1 (NF1).
• Granulocyte-macrophage colony-stimulating factor receptor-β (GM-CSFR-βc) is a receptor component for cytokines involved in immune responses and tumor promotion.

Purpose of the Study:

• To investigate the role of GM-CSFR-βc and GM-CSFR-α in a genetically engineered mouse model of neurofibroma.
• To determine the impact of deleting these receptors on tumor development, immune cell infiltration, and survival.

Main Methods:

• Utilized the Nf1^f/f; DhhCre mouse model for neurofibroma formation.
• Assessed expression of GM-CSFR-βc and GM-CSFR-α on tumor cells and immune cells.
• Analyzed tumor burden, immune cell populations (Iba1+, CD11c+), nerve structure, and mouse survival after genetic deletion of receptors.
• Performed proteome analysis of tumor lysates.

Main Results:

• GM-CSFR-βc expression was identified on PNF cells, macrophages, and dendritic cells.
• Genetic deletion of GM-CSFR-βc significantly reduced PNF numbers and associated Iba1+ macrophages and CD11c+ dendritic cells.
• Loss of GM-CSFR-α had no significant effect on tumor formation or immune cell infiltration.
• Deletion of either receptor did not improve mouse survival or nerve bundle structure.
• Proteome analysis revealed altered cytokine levels, suggesting compensatory mechanisms maintain a pro-inflammatory tumor environment.

Conclusions:

• GM-CSFR-βc signaling plays a modest role in plexiform neurofibroma development.
• The effect appears to be independent of its canonical ligand, GM-CSF.
• Immune cell infiltration, particularly macrophages and dendritic cells, is influenced by GM-CSFR-βc signaling in neurofibroma formation.