2. Academic Validation
  3. Necroptosis-dependent immunogenicity of cisplatin: implications for enhancing the radiation-induced abscopal effect

Necroptosis-dependent immunogenicity of cisplatin: implications for enhancing the radiation-induced abscopal effect

  • Clin Cancer Res. 2022 Nov 30;CCR-22-1591. doi: 10.1158/1078-0432.CCR-22-1591.
Ren Luo 1,  Kateryna Onyshchenko 2,  Liqun Wang 3,  Simone Gaedicke 4,  Anca-Ligia Grosu 5,  Elke Firat 6,  Gabriele Niedermann 7
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hosp, Freiburg im Breisgau, Germany.
  • 2 Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany. German Cancer Consortium (DKTK), Part, Freiburg im Breisgau, Germany.
  • 3 Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Freiburg im Breisgau, Germany.
  • 4 Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany, Freiburg, Germany.
  • 5 University of Freiburg, Freiburg, Germany.
  • 6 Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Freiburg, Germany.
  • 7 Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany., Freiburg, Germany.
PMID: 36449659 DOI: 10.1158/1078-0432.CCR-22-1591
Abstract

Purpose: 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.

Experimental design: Cisplatin, carboplatin, and the well-known immunogenic cell death (ICD) inducer oxaliplatin were compared for their potency to enhance the abscopal effect and induce IFN-I and extracellular ATP, danger signals of ICD. The hypothetical role of Necroptosis and associated DAMPs 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.

Results: 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 RIPK3-dependent tumor cell Necroptosis causing cytosolic mitochondrial DNA (mtDNA) release, initiating the cGAS-STING pathway and IFN-I secretion promoting T cell cross-priming by dendritic cells (DCs). 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.

Conclusions: 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.

Figures
Products