The NF1+/- Immune Microenvironment: Dueling Roles in Neurofibroma Development and Malignant Transformation

Abstract

Neurofibromatosis type 1 (NF1) is a common genetic disorder resulting in the development of both benign and malignant tumors of the peripheral nervous system. NF1 is caused by germline pathogenic variants or deletions of the NF1 tumor suppressor gene, which encodes the protein neurofibromin that functions as negative regulator of p21 RAS. Loss of NF1 heterozygosity in Schwann cells (SCs), the cells of origin for these nerve sheath-derived tumors, leads to the formation of plexiform neurofibromas (PNF)-benign yet complex neoplasms involving multiple nerve fascicles and comprised of a myriad of infiltrating stromal and immune cells. PNF development and progression are shaped by dynamic interactions between SCs and immune cells, including mast cells, macrophages, and T cells. In this review, we explore the current state of the field and critical knowledge gaps regarding the role of NF1(Nf1) haploinsufficiency on immune cell function, as well as the putative impact of Schwann cell lineage states on immune cell recruitment and function within the tumor field. Furthermore, we review emerging evidence suggesting a dueling role of Nf1+/- immune cells along the neurofibroma to MPNST continuum, on one hand propitiating PNF initiation, while on the other, potentially impeding the malignant transformation of plexiform and atypical neurofibroma precursor lesions. Finally, we underscore the potential implications of these discoveries and advocate for further research directed at illuminating the contributions of various immune cells subsets in discrete stages of tumor initiation, progression, and malignant transformation to facilitate the discovery and translation of innovative diagnostic and therapeutic approaches to transform risk-adapted care.

Keywords: Schwann cells; T cells; atypical neurofibroma; biomarkers; immune microenvironment; immunotherapy; macrophages; malignant peripheral nerve sheath tumor; mast cells; neurofibromatosis type 1 (NF1); plexiform neurofibroma.

Figure 1

Schematic illustrating stages of Schwann cell differentiation in relation to neurofibroma genesis. The top bar indicates the embryonic day at which the Schwann cells and their precursor first appear. The next series of bars indicates the stages at which various promoters drive Cre-mediated recombination of Nf1 in transgenic mouse models. The vertical bars denote whether the mouse model results in the formation of plexiform neurofibroma (PNF), cutaneous neurofibroma (CNF), or both. Schema adapted from Carroll et al. [65] and Le et al. [36]. Created with BioRender.com.

Figure 2

Complex cellular interactions between SCs and the tumor microenvironment shape neurofibroma development and malignant transformation. (A) Nf1-deficient SCs, the cells of origin for PNF, communicate via paracrine signaling and direct cell–cell contact with multiple Nf1+/- cell types within the tumor field, including neurons, macrophages, T cells, mast cells, fibroblasts, and endothelial cells, influencing neurofibroma pathogenesis. Adapted from Rhodes et al. [89]. (B) Malignant transformation of plexiform and atypical neurofibroma (ANNUBP) precursor lesions is associated with exclusion and/or exhaustion of infiltrating T cells, predominance of M2, pro-tumorigenic macrophages, and a decline in antigen presentation. Created with Biorender.com.