TMIC-65. GLOBAL PROFILING OF IMMUNE RESPONSE OF MICROGLIA AND MACROPHAGES IN PRECLINICAL MODEL OF GLIOBLASTOMA

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2019-11, Vol.21 (Supplement_6), p.vi262-vi262
• Main Authors: Walentynowicz, Kacper, Ochocka, Natalia, Segit, Paweł, Mieczkowski, Jakub, Wojtaś, Bartosz, Gielniewski, Bartłomiej, Kostyra, Kacper, Baluszek, Szymon, Kostkiewicz, Bogusław, Kaminska, Bozena
• Format: Article
• Language: English
• Subjects: Tumor Microenvironment
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noz175.1099

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor showing the poorest prognosis. Despite extensive research, no significant improvement in glioma therapy. GBM microenvironment has been shown to contribute to the aggressiveness of the tumor and influences overall survival. Tumor associated microglia and macrophages (TAMs) contribute to the biggest portion of tumor infiltrative cellular component, and may drive the immune response within the tumor. Their influence in the preclinical studies has not been fully described. Reliable animal models are crucial to facilitate translational research and drug discovery. In the present study, we employed animal xenograft model, where human GBM cells were stereotactically implanted into the mouse brain. Early and late stage responses of TAMs were studied using RNA-seq. Epigenetic changes within the TAMs were assessed using Assay for Transposase Accessible Chromatin sequencing (ATAC-seq) and Chromatin Immunoprecipitation sequencing (ChIP-seq) for four histone modifications (active transcription H3K4me3, H3K27ac, and repressed H3K9me3, H3K27me3) to further identify molecular alterations responsible for transcriptomic profiles. To facilitate translational discovery and heterogenous population of infiltrative cells, we isolated human CD11b cells from GBM patients and performed single cell RNA-seq (scRNAseq) using 10X Genomics platform. Moreover, we compared profiles of CD11b cells in the xenograft model with syngeneic immunocompetent model to further characterize commonly used models. Preliminary analysis shows critical differences between the models. Gain of global activation of genes has not been identified in the xenograft model. Differences in critical pathways in naïve microglia were identified, between the two studied models. Such global and extensive analysis allows us to compare preclinical models of GBM and clinical samples, and identify common pathways that can serve as potential therapeutic targets. This study was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 665735 (Bio4Med) and National Science Centre grant 2017/27/B/NZ3/01605.