66P - Metabolic regulation of GMP- and MDP-derived macrophages in glioblastoma

Background

Glioblastoma is the most common primary malignancy of the brain, affecting approximately 3 per 100 000 people, with a median overall survival of 15 months. Tumor-associated macrophages comprise up to 30% of the glioblastoma tumor microenvironment (TME) and consist of microglia and monocyte-derived macrophages (MDM). MDM arise from granulocyte-monocyte progenitors (GMP) or monocyte-dendritic cell progenitors (MDP). Our recent work identified a unique macrophage population expressing myeloperoxidase (MPO) and other GMP-associated genes associated with long-term survival in glioblastoma patients. ScRNA-seq analysis suggests that MPO+ macrophages may arise from GMPs and are metabolically distinct from MPO- MDM. Interestingly, adoptive transfer of GMP- versus MDP-derived monocytes into glioma-bearing mice had opposing effects on tumor growth. GMP-lineages specifically delayed tumor growth—aligning with our correlative findings in patients. The role of metabolic changes on the anti-tumor function of MDM of distinct developmental lineages remains unknown. We hypothesize that metabolic differences between GMP- and MDP-derived MDM may shift nutrient partitioning within the TME.

Methods

Bulk RNA-seq of GMP- and MDP-MDM was performed. To functionally assess metabolic differences between GMP- and MDP-MDM, Seahorse XFe96 analysis as well as metabolite analysis of conditioned media will be performed.

Results

Bulk RNA-seq of GMP- and MDP-MDM showed differential expression of many metabolic pathways, notably, a downregulation of the pentose phosphate pathway and aerobic respiration in GMP-MDM compared to MDP-MDM. Furthermore, co-culturing GMP- or MDP-MDM with GL261 glioma cell line suggests GMP-MDM are more phagocytic towards tumor cells. We will perform Seahorse XFe96 analysis and metabolite analysis of the conditioned media from GMP-MDM vs. MDP-MDM to investigate the functional impact of metabolic differences further.

Conclusions

Understanding how metabolic differences of MDM derived from different lineages shift nutrient competition in the TME will lead to a better understanding of the roles of macrophages in the TME.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.