After Nf1 loss in Schwann cells, inflammation drives neurofibroma formation

Jonathan S Fletcher, Jay Pundavela, Nancy Ratner, Jonathan S Fletcher, Jay Pundavela, Nancy Ratner

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.

Keywords: CXCR3; Interferon; Neurofibromatosis type 1; STAT3; T-cells; dendritic cells.

© The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Figures

Figure 1.
Figure 1.
Inflammation driven neurofibroma formation. After Nf1 loss in Schwann cells (SCs), a delay in phenotype occurs (Stage1). Subsequently, SCs show elevated growth factors/cytokine production (eg. CSF-1 and SCF), begin to show slight disruption of Remak bundles, and infiltration of mast cells. Macrophages are abundant by 2 months of age, and further cytokines are produced (eg CXCL10/IP-10), concurrent with occasional presence of CXCR3 positive dendritic cells (DCs) and T cells (Stage 2). By 4 months, small tumors form. These contain increased numbers of DCs, T cells. Macrophages remain abundant. Fibrosis is robust, and Remak bundle disruption dramatic. By 7 months, tumors enlarge; all features characterized at 4 months persist (Stage 3).
Figure 2.
Figure 2.
Potential immunotherapy targets in neurofibroma. In neurofibroma mouse models, the CXCL10/CXCR3 axis involving dendritic cells and T cells is critical in the early development of neurofibroma (~2 months). Macrophages contribute to neurofibroma formation via the involvement of STAT3 and CSF-1/CSF1R signaling. Inhibitory molecules targeting STAT3, CSF-1/CSF1R, and pegylated Interferon alpha 2b in established neurofibroma modestly inhibit tumor growth. MEK inhibition significantly shrinks most neurofibromas.

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