After Nf1 loss in Schwann cells, inflammation drives neurofibroma formation

Abstract

Plexiform neurofibromas (PNF) are peripheral nerve tumors caused by bi-allelic loss of NF1 in the Schwann cell (SC) lineage. PNF are common in individuals with Neurofibromatosis type I (NF1) and can cause significant patient morbidity, spurring research into potential therapies. Immune cells are rare in peripheral nerve, whereas in PNF 30% of the cells are monocytes/macrophages. Mast cells, T cells, and dendritic cells (DCs) are also present. NF1 mutant neurofibroma SCs with elevated Ras-GTP signaling resemble injury-induced repair SCs, in producing growth factors and cytokines not normally present in SCs. This provides a cytokine-rich environment facilitating PNF immune cell recruitment and fibrosis. We propose a model based on genetic and pharmacologic evidence in which, after loss of Nf1 in the SC lineage, a lag occurs. Then, mast cells and macrophages are recruited to nerve. Later, T cell/DC recruitment through CXCL10/CXCR3 drives neurofibroma initiation and sustains PNF macrophages and tumor growth. Stat3 signaling is an additional critical mediator of neurofibroma initiation, cytokine production, and PNF growth. At each stage of PNF development therapeutic benefit should be achievable through pharmacologic modulation of leukocyte recruitment and function.

RNA‐sequencing highlights differential regulated pathways involved in cell cycle and inflammation in orbitofacial neurofibromas

“…We previously documented increased ki67 proliferative indices in orbitofacial NF compared to NF developing in other sites ( 13 ), and there is emerging evidence that inflammation contributes to NF formation ( 31 ). Our gene set enrichment analyses also supported these findings.…”

Neurofibromatosis Type 1 Gene Alterations Define Specific Features of a Subset of Glioblastomas

“…In NF1-associated neurofibromas and MPNST, which are derived from peripheral glia, up to 30% of cells are macrophages. This finding led to the current hypothesis of neurofibroma formation in NF1: tumour initiation due to NF1 loss is followed by macrophage and mast cell recruitment, which is then followed by the recruitment of T and dendritic cells to enable tumour formation [ 102 ]. Half of NF1-associated low-grade gliomas were detected to harbour an immune signature, infiltrates of T cells, and increased neoantigens [ 15 ].…”

Secretome analysis of human schwann cells derived from malignant peripheral nerve sheath tumor

“…Gal‐3, also known as Mac‐2, is upregulated in SCs following nerve injury [30]. Indeed proteins expressed by SCs and involved in nerve injury/repair response are also expressed in neurofibroma formation [31].…”