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Necroptosis-dependent Immunogenicity of Cisplatin: Implications for Enhancing the Radiation-induced Abscopal Effect

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机构: [1]Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. [2]Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China. [3]Faculty of Biology, University of Freiburg, Freiburg, Germany. [4]German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany. [5]German Cancer Research Center (DKFZ), Heidelberg, Germany. [6]Laboratory of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics of NASU, Kyiv, Ukraine. [7]Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, P.R. China.
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Cisplatin is increasingly used in chemoimmunotherapy and may enhance the T cell-dependent radiation-induced abscopal effect, but how it promotes antitumor immunity is poorly understood. We investigated whether and why cisplatin is immunogenic, and the implications for the cisplatin-enhanced abscopal effect.Cisplatin, carboplatin, and the well-known immunogenic cell death (ICD) inducer oxaliplatin were compared for their potency to enhance the abscopal effect and induce type I IFN (IFN-I) and extracellular ATP, danger signals of ICD. The hypothetical role of necroptosis and associated damage-associated molecular patterns for cisplatin-induced ICD was investigated by inhibitors and knockout cells in vitro and in two tumor models in mice. A novel necroptosis signature for tumor immune cell infiltration and therapy response was developed.Cisplatin enhanced the abscopal effect more strongly than oxaliplatin or carboplatin. This correlated with higher induction of IFN-I and extracellular ATP by cisplatin, in a necroptosis-dependent manner. Cisplatin triggered receptor-interacting protein kinase 3 (RIPK3)-dependent tumor cell necroptosis causing cytosolic mitochondrial DNA (mtDNA) release, initiating the cyclic GMP-AMP synthase-stimulator of interferon genes pathway and IFN-I secretion promoting T-cell cross-priming by dendritic cells (DC). Accordingly, tumor cell RIPK3 or mtDNA deficiency and loss of IFN-I or ATP signaling diminished the cisplatin-enhanced abscopal effect. Cisplatin-treated tumor cells were immunogenic in vaccination experiments, depending on RIPK3 and mtDNA. In human tumor transcriptome analysis, necroptotic features correlated with abundant CD8+ T cells/DCs, sparse immunosuppressive cells, and immunotherapy response.Cisplatin induces antitumor immunity through necroptosis-mediated ICD. Our findings may help explain the benefits of cisplatin in chemo(radio)immunotherapies and develop clinical trials to investigate whether cisplatin enhances the abscopal effect in patients.©2022 American Association for Cancer Research.

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出版当年[2023]版:
大类 | 1 区 医学
小类 | 1 区 肿瘤学
最新[2023]版:
大类 | 1 区 医学
小类 | 1 区 肿瘤学
第一作者:
第一作者机构: [1]Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. [2]Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China. [3]Faculty of Biology, University of Freiburg, Freiburg, Germany. [4]German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany. [5]German Cancer Research Center (DKFZ), Heidelberg, Germany.
通讯作者:
通讯机构: [1]Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. [4]German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany. [5]German Cancer Research Center (DKFZ), Heidelberg, Germany. [*1]n, University of Freiburg, RobertKoch-Str. 3, Freiburg 79106, Germany
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