Projektbeschreibung
Vorhersage der Migration von Immunzellen in soliden Tumoren
Die Immunüberwachung hängt von der innewohnenden Fähigkeit der Immunzellen ab, zu verschiedenen Geweben zu wandern und immunbezogene Funktionen auszuführen. Die physikalischen Eigenschaften (Steifheit und Spannung) von Tumoren verhindern jedoch die wirksame Infiltration durch Immunzellen – eine Voraussetzung für antitumorale Immunantworten unter normalen Bedingungen sowie nach einer Immuntherapie. Im Rahmen des EU-finanzierten Projekts ICoMICS soll ein Modellierungsansatz entwickelt werden, mit dem sich vorhersagen lässt, auf welche Weise therapeutische Immunzellen wandern und mit der Mikroumgebung des Tumors interagieren. Die Forschenden werden 3D-Organoide solider Lungen-, Leber- und Bauchspeicheldrüsentumore mit spezifischen chemischen Modulatoren behandeln. Die so gewonnenen Daten werden daraufhin mit Informationen über die Gewebemechanik und Zellinteraktionen kombiniert. Die ICoMICS-Plattform wird dazu beitragen, die Ergebnisse der Immuntherapie zu verbessern.
Ziel
The immune system consists of a collection of cells with a high ability to migrate that work together to remove harmful foreign material from the body. Each immune cell can migrate between tissues, fulfilling specific functions in different microenvironments. However, this immune-surveillance response is not very effective in those tissues with a high non-physiological stiffness and a significant level of residual stresses, which are characteristics of solid tumors. Understanding the mechanisms that govern the cellular immune response to solid tumors is crucial to strengthen the development of novel immunotherapies. ICoMICS aims to develop a novel predictive modeling platform to investigate how therapeutic immune cells (TICs) sense, migrate and interact with cancerous cells and with the tumor microenvironment (TME). This platform will be built on two key pillars: in-vitro 3D tumor organoids and multicellular simulations, which will be combined and integrated by means of Bayesian optimization and machine learning techniques. On the one hand, cell culture microfluidic chips will be microfabricated, allowing continuous perfusion of chemical modulators through hydrogels (including decellularized matrices from murine stroma) inhabited by human tumor cells arranged to recreate 3D solid tumor organoids. On the other hand, an agent-based model will be developed to simulate cells as deformable objects, including cell-cell and cell-matrix interactions, combined with a continuum approach to model matrix mechanics and chemical reactions of cells, such as reactive oxygen species (ROS) and nutrients diffusion. Finally, ICoMICS will originally develop two innovative mechanistic-based immunotherapies. First, TICs will be subjected to high strains in micro-channels to induce them higher migration capacity. Second, TICs will be clustered as bio-bots, to ensure that they have improved functionality. All this research will be applied to 3 main solid tumors: lung, liver and pancreas.
Wissenschaftliches Gebiet
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
50009 Zaragoza
Spanien