Descripción del proyecto
Inmunoterapia derivada de tumores y sin células
Las vesículas extracelulares (VE) son partículas secretadas por las células que se emplean para la comunicación intercelular y el transporte de metabolitos, proteínas, lípidos y ácidos nucleicos. Aunque las VE derivadas de tumores (TEX, por sus siglas en inglés) son conocidas por su función inmunosupresora, cada vez hay más pruebas que sugieren que las células cancerosas pueden modular la biogénesis y el contenido de las TEX, alterando potencialmente su impacto en el sistema inmunitario. El equipo del proyecto IMMUNO-TEX, financiado por el Consejo Europeo de Investigación, se propone generar TEX como agentes anticancerígenos sin células para estimular la inmunidad contra el cáncer. Los investigadores estudiarán los mecanismos por los que las TEX se cargan con cargas específicas y aprovecharán la maquinaria celular para producir TEX inmunoestimuladoras. El trabajo propuesto permitirá superar la eficacia limitada y la resistencia ligada a ciertas inmunoterapias.
Objetivo
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.
Ámbito científico
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesbasic medicineimmunologyimmunotherapy
Palabras clave
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-ERC - HORIZON ERC GrantsInstitución de acogida
81675 Muenchen
Alemania