Immune microenvironment landscape and the role of neutrophils in glioblastoma

Abstract

Abstract Glioblastoma (GBM) is an aggressive, highly invasive primary brain tumor with near total fatality. Using a Cre-inducible lentiviral GBM mouse model we previously showed that gliomas can originate from terminally differentiated neurons and astrocytes, which can dedifferentiate to a stem cell-like state upon transformation. We believe that the tumor microenvironment (TME) may contribute to the process of tumor reprogramming. Although the majority of infiltrating cells in the tumor are peripheral macrophages and microglia, recent appreciation of the effects of neutrophils in cancer directed our efforts in understanding their role in GBM. Flow cytometry analysis revealed differences in the brain TME of both the innate and adaptive immune populations compared to healthy brain tissue, changes were also seen in spleen and bone marrow even at early stages of GBM development. The neutrophils population varies not only at different time-points but also between tumor subtypes. We believe neutrophils switch from anti-tumor to pro-tumor phenotype. Depletion of neutrophils right before tumor initiation accelerated the onset of the disease while co-transplantation of equal ratio of glioma cells and naïve neutrophils delayed the initiation of tumors lesions. In-vitro assays showed higher migration and formation of neutrophils extracellular traps (NETs) on exposure to glioma cells condition media or glioma derived exosomes. Our findings suggest neutrophils play a role in tumor initiation and progression, and further understanding the transition of neutrophils from anti-tumor to pro-tumor phenotype will shed light into new strategies to treat GBM.