68P - The role of systemic reprogramming of GMPs in improving outcomes in glioblastoma

Background

Glioblastomas are grade IV gliomas of the central nervous system associated with a median survival rate of less than 15 months. Therefore, research has been focused on better understanding the role of the tumor immune microenvironment, specifically macrophages (tissue-resident and monocyte-derived), which make up to 30% of the tumour. Using imaging mass cytometry, we have demonstrated that long-term survival in glioblastoma is associated with an accumulation of a rare subset of MPO+ monocyte-derived macrophages (MDM) within tumors, which appeared to originate from a shift in monocytosis. Transcriptomics analyses revealed that these macrophages exhibited heightened effector functions, potentially explaining their association with prolonged survival. This raises the question of whether monocyte developmental trajectories can be targeted as a therapeutic approach to promote the accumulation of MDM with elevated MPO, by reprogramming progenitor cells systemically.

Methods

To elucidate the effects of progenitor reprogramming on changes in the macrophage compartment, stimulants of myelopoiesis were administered. Bone marrow, blood, and spleen were characterized using flow cytometry. Furthermore, utilizing genetic and transplantable mouse models of glioblastoma (RCAS PDGFB-ink4a model and the GL261 model), durable reprogramming was induced, and tumor progression was assessed using MRI.

Results

In tumor-bearing and non-tumor-bearing mice, myelopoiesis was successfully reprogrammed as depicted in blood by increased proportions of Ly6C+ monocytes expressing high levels of TNF-α, IL-10, MPO, and CCR2. Similar changes were observed in the spleens of non-tumor-bearing mice. Studies using mouse models of glioblastoma indicated changes in survival and tumor volumes following progenitor reprogramming.

Conclusions

Systemic reprogramming of the myeloid compartment could have beneficial effects in preclinical models of glioblastoma.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Canadian Institutes of Health Research (CIHR).

Disclosure

All authors have declared no conflicts of interest.