TMIC-25. NEUTROPHIL-INDUCED GLIOBLASTOMA FERROPTOTIC CELL DEATH DEPENDS ON LC3-ASSOCIATED PHAGOCYTOSIS OF NEUTROPHILS BY GLIOBLASTOMA CELLS

Abstract

Abstract Glioblastoma multiforme (GBM) is the most aggressive and common type of primary adult brain cancer. Tumor necrosis is a histological hallmark of GBM and a poor prognostic factor for the disease. Although it is thought to result from chronic ischemia, the molecular mechanisms that induce tumor necrosis remain unclear. Previously, we reported that tumor-associated neutrophils (TANs) contribute to the generation of tumor necrosis through inducing ferroptosis in GBM cells. We showed that accumulation of lipid peroxides within GBM cells depends on neutrophil myeloperoxidase (MPO). The cell killing is associated with transfer of MPO-containing granules to GBM cells. (Yee et al., 2020, Nature Communications, DOI: 10.1038/s41467-020-19193-y). During further study of Neutrophil-induced glioblastoma ferroptotic cell death, we found that neutrophil engulfment by GBM cells is required for intercellular transfer of neutrophil contents and the upregulation of lipid peroxides in GBM cells. The engulfment process can be inhibited by RGDS peptides, which inhibit the function of RGDS-containing integrins. Furthermore, we used immunofluorescence imaging to show that internalized neutrophils colocalize to molecular components of the LC-3 associated phagocytosis (LAP) machinery. Disruption of these components either through pharmacological or genetic means rescues GBM cells from neutrophil-induced cell death. We then used an orthotopic xenograft GBM mouse model to demonstrate that disruption of the LAP machinery in tumor cells reduces tumor necrosis and improves survival. Altogether, this study identified a novel ferroptosis-inducing process, which can help to understand how neutrophils contribute to tumor necrosis in GBM. Additionally, the results suggested that targeting LAP may have therapeutic benefits for GBM treatment.