Tianqi Liu1, Chen Zhu1, Xin Chen1, Gefei Guan1, Cunyi Zou1, Shuai Shen1, Jianqi Wu1, Yuhang Wang2, Zhiguo Lin3, Ling Chen4, Peng Cheng1, Wen Cheng1, Anhua Wu1. 1. Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China. 2. The First Hospital of China Medical University, Shenyang, Liaoning, China. 3. Department of Neurosurgery, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China. 4. Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Medical School of Chinese PLA, Institute of Neurosurgery of Chinese PLA, Beijing, China.
Abstract
BACKGROUND: Immunosuppressive microenvironment is a major cause of immunotherapeutic resistance in glioma. In addition to secreting compounds, tumor cells under programmed cell death (PCD) processes release abundant mediators to modify the neighboring microenvironment. However, the complex relationship among PCD status, immunosuppressive microenvironment, and immunotherapy is still poorly understood. METHODS: Four independent glioma cohorts comprising 1,750 patients were enrolled for analysis. The relationships among PCD status, microenvironment cellular components, and biological phenotypes were fully explored. Tissues from our hospital and experiments in vitro and in vivo were used to confirm the role of ferroptosis in glioma. RESULTS: Analyses to determine enriched PCD processes showed that ferroptosis was the main type of PCD in glioma. Enriched ferroptosis correlated with progressive malignancy, poor outcomes, and aggravated immunosuppression in glioblastoma (GBM) patients. Enhanced ferroptosis was shown to induce activation and infiltration of immune cells but attenuated antitumor cytotoxic killing. Tumor-associated macrophages (TAMs) were found to participate in ferroptosis-mediated immunosuppression. Preclinically, ferroptosis inhibition combined with Programmed Cell Death 1 (PD-1) and Programmed Cell Death Ligand-1 (PD-L1) blockade generated a synergistic therapeutic outcome in GBM murine models. CONCLUSIONS: This work provides a molecular, clinical, and biological landscape of ferroptosis, suggesting a role of ferroptosis in glioma malignancy and a novel synergic immunotherapeutic strategy that combines immune checkpoint blockade treatment with ferroptosis inhibition.
BACKGROUND: Immunosuppressive microenvironment is a major cause of immunotherapeutic resistance in glioma. In addition to secreting compounds, tumor cells under programmed cell death (PCD) processes release abundant mediators to modify the neighboring microenvironment. However, the complex relationship among PCD status, immunosuppressive microenvironment, and immunotherapy is still poorly understood. METHODS: Four independent glioma cohorts comprising 1,750 patients were enrolled for analysis. The relationships among PCD status, microenvironment cellular components, and biological phenotypes were fully explored. Tissues from our hospital and experiments in vitro and in vivo were used to confirm the role of ferroptosis in glioma. RESULTS: Analyses to determine enriched PCD processes showed that ferroptosis was the main type of PCD in glioma. Enriched ferroptosis correlated with progressive malignancy, poor outcomes, and aggravated immunosuppression in glioblastoma (GBM) patients. Enhanced ferroptosis was shown to induce activation and infiltration of immune cells but attenuated antitumor cytotoxic killing. Tumor-associated macrophages (TAMs) were found to participate in ferroptosis-mediated immunosuppression. Preclinically, ferroptosis inhibition combined with Programmed Cell Death 1 (PD-1) and Programmed Cell Death Ligand-1 (PD-L1) blockade generated a synergistic therapeutic outcome in GBM murine models. CONCLUSIONS: This work provides a molecular, clinical, and biological landscape of ferroptosis, suggesting a role of ferroptosis in glioma malignancy and a novel synergic immunotherapeutic strategy that combines immune checkpoint blockade treatment with ferroptosis inhibition.
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