Necroptosis-dependent Immunogenicity of Cisplatin: Implications for Enhancing the Radiation-induced Abscopal Effect.
Clin Cancer Res
; 29(3): 667-683, 2023 02 01.
Article
in En
| MEDLINE
| ID: mdl-36449659
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. EXPERIMENTALDESIGN:
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.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 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.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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neoplasms
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Clin Cancer Res
Journal subject:
NEOPLASIAS
Year:
2023
Document type:
Article
Affiliation country: