Dissecting the heterogeneity and functions of the glioblastoma myeloid compartment Ana Rita Pombo Antunes1,2, Liesbet Martens3, Karen De Vlaminck1,2, Hannah Van Hove1,2, Sofie De Prijck4, Niels Vandamme4 Signe Schmidt Kjølner Hansen1,2, Roosmarijn E Vandenbroucke5, Martin Guilliams4, Yvan Saeys4, Jo Van Ginderachter1,2, Kiavash Movahedi1,2 1Myeloid Cell Immunology Lab, VIB Inflammation Research Center; 2Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Belgium; 3Data Mining and Modelling for Biomedicine Group, VIB Inflammation Research Center, Ghent University, Belgium; 4Lab of Immunoregulation, VIB Inflammation Research Center, Ghent University, Belgium; 5 Lab of Barriers in Inflammation, VIB Inflammation Research Center, Ghent University, Belgium
Glioblastoma multiforme (GBM) is an invariably fatal primary malignant brain tumor. The GBM immune infiltrate is recognized as a key player in tumor progression, potentially exerting both pro- and anti-tumoral functions. A better understanding of these cells is imperative for the development of more efficient therapies. We have relied on single-cell RNA sequencing to unravel the complexity of the glioblastoma immune landscape. This showed that GBM tumors contain a highly heterogeneous immune compartment with a plethora of transcriptionally distinct subpopulations. The largest fraction of tumor-infiltrating immune cells were of myeloid origin, consisting of macrophages and conventional dendritic cells. Interestingly, we identified multiple distinct tumor associated macrophage (TAM) subsets, of which the transcriptional signatures were in part driven by their ontogeny. Using trajectory inference of thousands of single cells, we uncovered the transcriptional dynamics of monocyte to macrophage differentiation in GBM tumors. In addition, multi-parametric flow cytometry allowed for cell sorting of the various TAM and cDC subsets, which was followed by an extensive functional profiling. This showed clear differences in T-cell stimulatory and suppressive capacities, phagocytic activity and pro-angiogenic potential, which was driven by TAM ontogeny and differentiation state. Finally, we show that blocking the infiltration of monocyte-derived TAMs impaired tumor progression. Together, our data help to unravel the complexities of the GBM immune compartment, paving the way for strategies to optimally “re-educate” specific TAM or cDC subsets to tilt the balance towards tumor eradication.
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