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Dynamical Boolean Modeling of Immunogenic Cell Death.
Checcoli, Andrea; Pol, Jonathan G; Naldi, Aurelien; Noel, Vincent; Barillot, Emmanuel; Kroemer, Guido; Thieffry, Denis; Calzone, Laurence; Stoll, Gautier.
Afiliación
  • Checcoli A; Institut de Biologie de l'ENS (IBENS), Département de Biologie, École Normale Supérieure, CNRS, INSERM, Université PSL, Paris, France.
  • Pol JG; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Institut Universitaire de France, Paris, France.
  • Naldi A; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
  • Noel V; Institut de Biologie de l'ENS (IBENS), Département de Biologie, École Normale Supérieure, CNRS, INSERM, Université PSL, Paris, France.
  • Barillot E; Institut Curie, PSL Research University, Paris, France.
  • Kroemer G; INSERM, U900, Paris, France.
  • Thieffry D; MINES ParisTech, PSL Research University, CBIO-Centre for Computational Biology, Paris, France.
  • Calzone L; Institut Curie, PSL Research University, Paris, France.
  • Stoll G; INSERM, U900, Paris, France.
Front Physiol ; 11: 590479, 2020.
Article en En | MEDLINE | ID: mdl-33281620
As opposed to the standard tolerogenic apoptosis, immunogenic cell death (ICD) constitutes a type of cellular demise that elicits an adaptive immune response. ICD has been characterized in malignant cells following cytotoxic interventions, such as chemotherapy or radiotherapy. Briefly, ICD of cancer cells releases some stress/danger signals that attract and activate dendritic cells (DCs). The latter can then engulf and cross-present tumor antigens to T lymphocytes, thus priming a cancer-specific immunity. This series of reactions works as a positive feedback loop where the antitumor immunity further improves the therapeutic efficacy by targeting cancer cells spared by the cytotoxic agent. However, not all chemotherapeutic drugs currently approved for cancer treatment are able to stimulate bona fide ICD: some commonly used agents, such as cisplatin or 5-fluorouracil, are unable to activate all features of ICD. Therefore, a better characterization of the process could help identify some gene or protein candidates to target pharmacologically and suggest combinations of drugs that would favor/increase antitumor immune response. To this end, we have built a mathematical model of the major cell types that intervene in ICD, namely cancer cells, DCs, CD8+ and CD4+ T cells. Our model not only integrates intracellular mechanisms within each individual cell entity, but also incorporates intercellular communications between them. The resulting cell population model recapitulates key features of the dynamics of ICD after an initial treatment, in particular the time-dependent size of the different cell types. The model is based on a discrete Boolean formalism and is simulated by means of a software tool, UPMaBoSS, which performs stochastic simulations with continuous time, considering the dynamics of the system at the cell population level with appropriate timing of events, and accounting for death and division of each cell type. With this model, the time scales of some of the processes involved in ICD, which are challenging to measure experimentally, have been predicted. In addition, our model analysis led to the identification of actionable targets for boosting ICD-induced antitumor response. All computational analyses and results are compiled in interactive notebooks which cover the presentation of the network structure, model simulations, and parameter sensitivity analyses.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Front Physiol Año: 2020 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Suiza

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Front Physiol Año: 2020 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Suiza