Abstract
Tumor-associated macrophages (TAMs) constitute up to 50% of tumor bulk in glioblastoma (GBM) and play an important role in tumor maintenance and progression. The recently discovered differences between invading tumour periphery and hypoxic tumor core implies that macrophage biology is also distinct by location. This may provide further insight into the observed treatment resistance to immune modulation. We hypothesize that macrophage activation occurs through processes that are distinct in tumor periphery versus core. We therefore investigated regional differences in TAM recruitment and evolution in GBM by combining open source single cell and bulk gene expression data. We used single cell gene expression data from 4 glioblastomas (total of 3589 cells) and 122 total bulk samples obtained from 10 different patients. Cell identity, ontogeny (bone-marrow derived macrophages-BMDM vs microglia), and macrophage activation state were inferred using verified gene expression signatures. We captured the spectrum of immune states using cell trajectory analysis with pseudotime ordering. In keeping with previous studies, TAMs carrying BMDM identity were more abundant in tumor bulk while microglia-derived TAMs dominated the tumor periphery across all macrophage activation states including pre-activation. We note that core TAMs evolve towards a pro-inflammatory state and identify a subpopulation of cells based on a gene program exhibiting strong, opposing correlation with Programmed cell Death-1 (PD-1) signaling, which may correlate to their response to PD-1 inhibition. By contrast, peripheral TAMs evolve towards anti-inflammatory phenotype and contains a population of cells strongly associated with NFkB signaling. Our preliminary analysis suggests important regional differences in TAMs with regard to recruitment and evolution. We identify regionally distinct and potentially actionable cell subpopulations and advocate the need for a multi-targeted approach to GBM therapeutics.
Highlights
Tumor-associated macrophages (TAMs) constitute up to 50% of tumor bulk in glioblastoma (GBM) and play an important role in tumor maintenance and progression
To further explore the Uniform Manifold Approximation and Projection (UMAP) clusters we evaluated the metagene expression of a general macrophage gene signature[18] to compare with known immune cell annotations (Fig. 1F), as well as signatures implicated in bone-marrow-derived macrophages (BMDM) and microglia-derived macrophages[19] (Fig. 1G,H)
We found that TAMs in the tumour core mostly originate from the bone marrow derived pool whereas those in the tumour periphery are largely derived from microglial cells, supporting prior r esearch[19]
Summary
Tumor-associated macrophages (TAMs) constitute up to 50% of tumor bulk in glioblastoma (GBM) and play an important role in tumor maintenance and progression. The recently discovered differences between invading tumour periphery and hypoxic tumor core implies that macrophage biology is distinct by location. This may provide further insight into the observed treatment resistance to immune modulation. We hypothesize that macrophage activation occurs through processes that are distinct in tumor periphery versus core. We investigated regional differences in TAM recruitment and evolution in GBM by combining open source single cell and bulk gene expression data. Recent studies have implied distinct regional abundance for TAMs, with BMDM being dominant in tumor core while microglia are more prevalent in the invading e dge[7]. We hypothesize distinct region-specific recruitment, activation, and maturation programs
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