Abstract 5994: Neutrophils internalized through LC3-associated phagocytosis trigger tumor ferroptotic cell death in glioblastoma

Abstract

Abstract Necrosis is commonly found in various solid tumors and predicts worse outcome. Chronic ischemia can initiate tumor necrosis, however, how the damaged tissue further expands is unclear. Previous studies found that neutrophils associate with necrosis and could contribute the necrosis development in glioblastoma (GBM) through transferring myeloperoxidase-containing granules into tumor cells and inducing tumor cell ferroptosis. How the neutrophilic granule transfer occurs is unknown. Here, through an unbiased small molecule screen, we found that statins can inhibit the neutrophil-induced tumor cell death through blocking the neutrophilic content transfer into tumor cells. Surprisingly, we found that neutrophils are engulfed by tumor cells before they are fragmented and release the MPO-containing contents in tumor cells. This process is through LC3-associated phagocytosis (LAP) and can be blocked by inhibiting the Vps34-UVRAG-containing PI3K complex. Inhibition of MPO or depletion of Vps34 in an orthotopic xenograft GBM mouse model showed that necrosis formation is reduced, and the tumor-bearing mice can survive longer. Therefore, this study revealed that the neutrophilic granule transfer is through LAP-mediated neutrophil internalization, which then trigger tumor ferroptotic cell death in glioblastoma. Blocking this process may improve prognosis of GBM. Citation Format: Tong Y. Lu, Patricia P. Yee, Stephen Y. Chih, Dawit G. Aregawi, Michael J. Glantz, Brad E. Zacharia, Hong-Gang Wang, Wei Li. Neutrophils internalized through LC3-associated phagocytosis trigger tumor ferroptotic cell death in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5994.