Description du projet
Immunothérapie sans cellules dérivée de tumeurs
Les vésicules extracellulaires (VE) sont des particules sécrétées par les cellules qui servent à la communication intercellulaire et à l’administration de métabolites, de protéines, de lipides et d’acides nucléiques. Bien que les VE dérivées de tumeurs (TEX) soient connues pour leur fonction immunosuppressive, de nouvelles données suggèrent que les cellules cancéreuses peuvent moduler la biogenèse et le contenu des TEX, ce qui pourrait modifier leur impact sur le système immunitaire. Financé par le Conseil européen de la recherche, le projet IMMUNO-TEX propose de générer des TEX en tant qu’agents anticancéreux sans cellules afin de stimuler l’immunité anticancéreuse. Les chercheurs étudieront les mécanismes de chargement spécifique des TEX et exploiteront la machinerie cellulaire pour produire des TEX immunostimulants. Le travail proposé permettra de surmonter les limites de l’efficacité et de la résistance associées à certaines immunothérapies.
Objectif
Tumor immunotherapy with immune checkpoint inhibitors (ICI) has unprecedented therapeutic potential, but its success is limited to a minority of patients with preexisting antitumor T-cell immunity. For patients with poorly-immunogenic tumors, combinatorial immunotherapies are urgently needed. With a vast and bioactive cargo (proteins, lipids, nucleic acids), extracellular vesicles (EVs) have intrinsic property to regulate complex pathways in distant target cells. Even though they can transfer tumor antigens which potentially activate T cells, tumor-derived EVs (TEX) have mainly been associated with immunosuppressive function. I have recently identified innate immune pathways within tumor cells that regulate TEX biogenesis and immunogenicity. This allows for the first time to “force” tumor cells to release a defined immunostimulatory (is)TEX product. The unconventional objective of IMMUNO-TEX is to generate a platform for the pioneering therapeutic use of tumor-derived isTEX as multifunctional cell-free anticancer agents. isTEX combine a cargo of a plethora of patient-specific tumor (neo-) antigens and immunostimulatory constituents within a single, non-toxic delivery vehicle, that allows for efficient priming of tumor antigen-specific T cells. The ability to harness the vast potential of isTEX is directly interwoven with a more detailed mechanistic understanding how tumor-specific cargo packaging in EVs occurs and how they alter immune cell function. Therefore, IMMUNO-TEX will identify and exploit the intracellular machinery in tumor cells for optimal isTEX generation, investigate how isTEX enable an immune-supportive tumor microenvironment, and validate isTEX to overcome ICI resistance in relevant murine and human model systems. Hereby, IMMUNO-TEX will eliminate current limitations of ICI immunotherapy by rationally designed combination with isTEX to allow responsiveness in patients with poorly immunogenic tumors.
Champ scientifique
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesbasic medicineimmunologyimmunotherapy
Mots‑clés
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
HORIZON-ERC - HORIZON ERC GrantsInstitution d’accueil
81675 Muenchen
Allemagne