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

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.