Modelling of Immunogenic Cell Death (ModICeD)
This project is a collaboration between the group of Denis Thieffry at IBENS and the group of Jonathan Pol à Centre de Recherche Les Cordeliers (CRC). It is financed by the MIC (Mathématiques et Informatique) 2020 – Cancer – INSERM
As opposed to standard apoptosis that is tolerogenic, immunogenic cell death (ICD) describes a type of apoptosis that elicits an adaptive immune response. ICD has been characterized in malignant cells following cytotoxic interventions such as chemotherapy or radiotherapy. A series of reactions, from the release of danger signals to the activation of an immune response, triggers a positive feedback loop where the antitumor immunity further improves the therapeutic efficacy by targeting cancer cells spared by the cytotoxic agent. However, some common treatments (cisplatin or 5-fluorouracil) are unable to activate all features of ICD. Therefore, a better characterization of the process could help identify some gene candidates to target and suggest combinations of drugs that would increase antitumor immune response.
The project will explore three axes: (1) the construction of a logical model considering cancer cells, dendritic cells (DCs), and CD8+ and CD4+ T lymphocytes, based on the published knowledge and calibrated on experimental data. Our model will integrate intracellular mechanisms within each individual cell entity, but also intercellular communications; (2) the experimental validation which will be two-fold: early in the project as a mean to fit the model to data on murine model of fibrosarcoma including temporal data, and later to validate the predictions of the model on breast cancer cell lines and breast cancer murine models; and (3) the development of a cell population tool, PopMaBoSS, which will enable stochastic simulations with continuous time, considering the dynamics of the system at the cell population level with appropriate timing of events, death and division of each cell type.
Ultimately, the project will lead to the delineation of specific sets of perturbations enabling the fostering of ICD in the course of anticancer therapies.