P12.07.B THE POST-SURGICAL MICROENVIRONMENT OF GLIOBLASTOMA AS THERAPEUTIC TARGET TO AVOID RECURRENCES

Abstract

Abstract BACKGROUND Glioblastoma (GBM) is an incurable primary brain tumour. Most GBM patients undergo surgery prior to chemoradiation, but recurrences inevitably lead to patient death. The brain physiological regenerative responses following tumor debulking have a beneficial role in the healing process. However, they also evoke characteristic time-dependent peritumoral immune responses which can promote the formation of recurrences. The crosstalk between glial, immune and GBM cells at the surgical borders and their impact on recurrences still lacks appropriate characterization. This project aims at dissecting the GBM post-surgical microenvironment (SMe) over time and space to identify therapeutic targets and develop tailored GBM therapies to avoid the onset of recurrences. MATERIAL AND METHODS We developed a tumor resection model in transgenic mice bearing GL261 tumors and established a chronic intracranial window post-surgery by biphotonic imaging. Nuclear imaging was performed at defined time points using 99mTc-DTPA, 68Ga-RGD and 18F-FDG to evaluate neuroinflammation, neoangiogenesis, infiltrating tumor cells metabolism and BBB permeability. The dynamics of the inflammatory landscape following surgery was characterized by blood sampling and post-mortem analysis on brain samples (peripheral and local immunophenotyping by multiparametric flow cytometry; brain clearing and ultramicroscopy). RESULTS We analyzed the dynamics of recruitment and localization of immune cells coming to the resection site from the brain parenchyma or from the periphery from surgery to recurrence. BBB disruption was observed post-surgery followed by a recovery within three days. Based on the results obtained we finally tested a therapeutic approach combining the local administration of lauroyl-gemcitabine lipid nanocapsules hydrogel with the repeated systemic administration of a SMAC-mimetic drug showing an increase in survival of GBM-bearing mice. CONCLUSION This comprehensive study expands the knowledge on the SMe by analyzing the impact of BBB disruption on immune cells recruitment and the role of lymphoid and myeloid populations - as well as macrophages and microglia - on the onset of tumor recurrences. Moreover, it proposes a rationally designed combinatory treatment able to target the identified cellular targets to delay or inhibit the onset of recurrences.