Abstract A04: An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system

Abstract

Neurofibromas are benign peripheral nerve tumors driven by NF1 loss in Schwann cells (SCs). Current evidence suggests that an inflammatory environment is critical for neurofibroma development and growth, however the roles of intercellular interactions between SCs and other cells in neurofibroma microenvironment are not clear yet. Neurofibromas contain numerous macrophages. We analyzed gene expression in FACS-sorted SCs and macrophages from wild type nerve and neurofibroma. Nerve macrophage transcriptomes differed from previously defined macrophage sub-populations. In 1-month-old Nf1 mutant nerve, neither SCs nor macrophages significantly differed from their counterparts in normal mice. In 7-month-old neurofibromas, macrophages showed significantly altered gene expression, as did neurofibroma SCs. Computational reconstruction of SC-macrophage molecular networks based on the gene expression data revealed extensive inflammatory-associated signaling and possible interplay between macrophages and Schwann cells. Among these were previously implicated pathways and novel paracrine and autocrine loops involving cytokines, chemokines, and growth factors. Specifically, the data predicted increased cytokine expression and imbalanced type-I/type-II interferon signaling, which were confirmed by protein profiling, and normalized in neurofibroma-bearing mice treated with PEGylated interferon-α2b. These studies identify Nf1 mutant SCs interactions with macrophages, which result in chronic inflammation and neurofibroma, and provide a system in which to study early changes in benign tumorigenesis. Citation Format: Kwangmin Choi, Kakajan Komurov, Jonathan S. Fletcher, Edwin Jousma, Jose A. Cancelas, Jianqiang Wu, Nancy Ratner. An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A04.