Descrizione del progetto
Immunoterapia di derivazione tumorale senza cellule
Le vescicole extracellulari (EV) sono particelle secrete dalle cellule e utilizzate per la comunicazione cellula-cellula e il trasporto di metaboliti, proteine, lipidi e acidi nucleici. Sebbene le EV di derivazione tumorale (TEX) siano note per la loro funzione immunosoppressiva, sempre più evidenze suggeriscono che le cellule tumorali possono modulare la biogenesi e il contenuto delle TEX, alterando potenzialmente il loro impatto sul sistema immunitario. Finanziato dal Consiglio europeo della ricerca, il progetto IMMUNO-TEX propone di generare TEX come agenti antitumorali privi di cellule per stimolare l’immunità antitumorale. I ricercatori studieranno i meccanismi con cui i TEX vengono caricati con un carico specifico e sfrutteranno il meccanismo cellulare per produrre TEX immunostimolanti. Lo studio proposto supererà l’efficacia limitata e la resistenza legata ad alcune immunoterapie.
Obiettivo
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.
Campo scientifico
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesbasic medicineimmunologyimmunotherapy
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
81675 Muenchen
Germania