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

Abstract

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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 <i>in vitro</i> and in two tumor models in mice. A novel necroptosis signature for tumor immune cell infiltration and therapy response was developed.</p>Results:<p>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<sup>+</sup> T cells/DCs, sparse immunosuppressive cells, and immunotherapy response.</p>Conclusions:<p>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.</p></div>