Glioma cell-intrinsic genetic events shape the infiltrating immune tumor landscape

Glioblastoma (GBM) is an aggressive, highly invasive primary brain tumor with near total fatality. GBM remains a challenge for prognosis despite intensive therapies. We use a Cre-inducible lentiviral vector-based mouse model of GBM that recapitulates the pathophysiology of the human disease. Transduction by oncogenic lentiviral-vectors, irrespective of the initiating cell population share a common stem-like cancer cell population that can originate from dedifferentiation/reprogramming of mature transformed cells. We believe that the tumor microenvironment (TME) may contribute to tumor reprogramming. This novel GBM mouse model allowed us to reveal the immune TME from initiation to endpoint of the disease.

Flow cytometric analysis showed differences in the brain TME, mostly innate immune populations compared to healthy brain. Changes were seen in spleen and bone marrow within 2weeks. The neutrophil population was found to vary not only at various time-points but also between the molecular subtypes. Recent appreciation of the effects of neutrophils in cancer directed our efforts in understanding their role in GBM. With bone-marrow neutrophils we observed higher migration of neutrophils from ‘tumor-bearing’ mice (eNΦ) on exposure to glioma cells condition media but lower cytotoxicity and NETosis as compared to WT neutrophils (nNΦ). WINN-type assay by intracranial injection of glioma cells with nNΦ or eNΦ reduced tumor burden only with nNΦ. The dynamic changes in the TME and the differences in response of eNΦ to nNΦ suggests a cross-talk.Further understanding the switch of eNΦ to pro-tumorigenic will facilitate the development of novel strategies aiming at reprogramming the TME as an additional approach to attack cancer.