胶质瘤
肿瘤微环境
免疫疗法
免疫抑制
癌症研究
免疫系统
程序性细胞死亡
恶性肿瘤
免疫学
细胞凋亡
生物
遗传学
生物化学
作者
Tianqi Liu,Chen Zhu,Xin Chen,Gefei Guan,Cunyi Zou,Shuai Shen,Jianqing Wu,Yuhang Wang,Zhiguo Lin,Ling Chen,Cheng Peng,Wen Cheng,Anhua Wu
出处
期刊:Neuro-oncology
[Oxford University Press]
日期:2022-02-11
卷期号:24 (7): 1113-1125
被引量:40
标识
DOI:10.1093/neuonc/noac033
摘要
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.
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