ID #1022 Myeloid mimicry in NF1 high-grade glioma: A CD74-positive antigen presenting glioma tumor cell population in primary human tumors and murine models

Abstract

Compared to the general population, individuals with Neurofibromatosis Type 1 have a 50-fold higher risk of developing a high-grade glioma (HGG) in their lifetime. Despite improved understanding of the molecular and cellular drivers of these neoplasms, we have yet to translate this knowledge into therapies that improve overall survival. One limitation has been the paucity of in vivo models for drug testing within this population. We generated 3 distinct glioma stem cell lines from spontaneous high-grade gliomas arising in mice with Nf1 and Trp53 mutations in cis (NPcis) and characterized the allografts resulting from one Nf1-glioma stem cell line (Nf1-HGG17) by snRNA-seq. Because our cell lines are grown in stem cell media, there is an inherent reduction of the in vivo present HGG differentiation states, resulting in a more uniform population consisting of oligodendrocyte precursor-like and neural-like cells. However, orthotopic allografts of Nf1-HGG17 regained the other differentiation states typically observed in HGG and GBM (neuronal progenitor cell-like and astrocyte-like). About half of neoplastic cells cluster separately from these classical groups and highly express genes for antigen presentation machinery (including CD74) which we also observed in patient samples. These CD74 expressing glioma cells take on a myeloid mimicking phenotype that is pro-tumorigenic and could be an important population to target therapeutically. We also find that heterozygosity of Nf1 within the tumor microenvironment does not cause marked changes in the immune tumor microenvironment, gene expression, or differentiation states of neoplastic cells. These data indicate that allografted HGG lines from NPcis mice are an effective model of NF1-HGG, mimicking the complexity observed in human HGG, that can be used for larger scale in vivo drug screening and evaluation.