Exploring the Longitudinal Glioma Microenvironment Landscape Uncovers Reprogrammed Pro-Tumorigenic Neutrophils in the Bone Marrow

Abstract

Glioblastoma (GBM) is known for its persistence and recurrence despite current treatment modalities, mainly attributed to GBM high inter- and intra-tumor heterogeneity. Recent high-scale multi-omics studies have mapped the immune tumor microenvironment (TME) in great detail, uncovering different immune compositions in GBM. However, a temporal comprehensive knowledge of the TME from initiation of the disease remains sparse till today. We used Cre-inducible lentiviral murine GBM models to compare the cellular evolution of the immune TME in tumors initiated from different oncogenic drivers and different cell-of-origin. While several myeloid cell populations showed variation among the different tumors, we identified neutrophils to infiltrate early during tumor progression primarily in the mesenchymal (MES) GBM subtype. Depleting neutrophils in-vivo at the onset of disease accelerated tumor growth and reduced the median overall survival of mice bearing MES GBM. We show that as tumor progresses, bone marrow derived neutrophils are skewed toward a phenotype associated with pro-tumorigenic processes such as angiogenesis, cell migration, decreased cytotoxicity, and immunosuppressive T cell effects. Our findings suggest GBM can remotely regulate systemic myeloid differentiation within the bone marrow to generate neutrophils pre-committed to a tumor-supportive phenotype. This work further reveals plasticity in the systemic immune host microenvironment, suggesting an additional point of intervention in GBM treatment.