AUTHOR=McLean Dalton T. , Meudt Jennifer J. , Lopez Rivera Loren D. , Schomberg Dominic T. , Pavelec Derek M. , Duellman Tyler T. , Buehler Darya G. , Schwartz Patrick B. , Graham Melissa , Lee Laura M. , Graff Keri D. , Reichert Jamie L. , Bon-Durant Sandra S. , Konsitzke Charles M. , Ronnekleiv-Kelly Sean M. , Shanmuganayagam Dhanansayan , Rubinstein C. Dustin TITLE=Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model JOURNAL=Frontiers in Oncology VOLUME=13 YEAR=2023 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1253659 DOI=10.3389/fonc.2023.1253659 ISSN=2234-943X ABSTRACT=

Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1+/CD274+ (PD-L1)+ dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration.