87P - Macrophage ontogeny underlies functional programs and drives brain tumor progression

Background

Glioblastoma is the most common and aggressive primary brain cancer with an overall survival of 15 months despite aggressive cytotoxic treatments. Therefore, identifying new therapeutic targets within the tumor microenvironment (TME) is critical for improving patient outcomes. In glioblastoma, macrophages make up to 30% of the bulk tumor, which include both yolk-sac derived tissue-resident microglia and monocyte-derived macrophages (MDMs) that are recruited from the bone marrow during inflammation. During hematopoiesis, MDMs can arise from granulocyte-monocyte progenitors (GMPs) or monocyte-dendritic cell progenitors (MDPs), which give rise to neutrophil-like or dendritic cell-like lineages, respectively. Although MDMs as a whole are often considered tumor-promoting, the functional role of specific MDM ontogenies is not known. Our recent study identified a subset of MPO+ MDMs associated with better overall survival, enhanced cytotoxic function, and gene expression suggestive of a GMP origin. Therefore, the aim of this study is to characterize the role of MDM ontogeny in brain tumor progression.

Methods

Using a combination of RNA-sequencing, in vitro functional assays and in vivo fate-mapping tools, we assessed the functional role of macrophage ontogeny in glioblastoma models. Additionally, we adoptively transferred monocytes cultured ex vivo from distinct developmental origins to trace their recruitment to tumors and assess the subsequent impact on tumor growth.

Results

Interestingly, macrophage ontogeny was associated with differences in MHC I-mediated and MHC II-mediated antigen presentation as well as unique profile of cytokines and chemokines, including MPO. Additionally, we found differences in phagocytosis towards glioma cells and upregulation of different inflammatory pathways. Importantly, adoptive transfer of monocytes of distinct ontogenies had opposing effects on brain tumor progression and resulted in significant changes to the TME and peripheral immune system.

Conclusions

Our findings shed light on the developmental origins of brain tumor MDMs and their putative regulatory impact in the TME.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Brain Tumour Foundation of Canada.

Disclosure

All authors have declared no conflicts of interest.