Descrizione del progetto
Scoprire nuove dimensioni della regolazione immunometabolica
La ricerca dimostra che, quando i leucociti si attivano correttamente, i linfociti T reattivi al tumore e altri tipi di cellule del sistema immunitario possono distruggere i tumori. Si tratta di una svolta importante nel trattamento del cancro. Il progetto MitoGuide, finanziato dall’UE, si concentrerà su come il ripristino dell’adeguatezza metabolica dei linfociti T rappresenti una strategia promettente per rafforzare l’immunità antitumorale. Affinché questa strategia abbia successo, è necessario comprendere i meccanismi di fondo utilizzati dalle cellule tumorali per abolire l’adeguatezza metabolica dei linfociti T e il modo in cui la programmazione metabolica controlla le funzioni dei linfociti T. Il progetto intende chiarire in che modo le cellule tumorali influenzino la dinamica mitocondriale dei linfociti T e definire le regolazioni immunometaboliche inesplorate delle funzioni dei linfociti T controllate dai mitocondri.
Obiettivo
Cancer immunotherapies harnessing the tumoricidal activity of tumor-reactive T cells represent a major breakthrough in the current paradigm for treating cancer patents. However, the highly immunosuppressive tumor microenvironments found in solid tumors present challenges by restricting the tumoricidal functions and metabolic fitness of infiltrating tumor-reactive T cells. Given that the activation-induced metabolic switch is tightly intertwined with T cell activities, restoring the metabolic fitness of T cells represents a promising strategy for strengthening anti-tumor immunity. However, the success of this strategy relies on our understanding of the underlying mechanisms utilized by tumor cells to abolish the metabolic fitness of T cells, and of how metabolic programming controls T cell functions. Based on our preliminary results, we postulate that tumor cells disrupt the mitochondrial dynamics of tumor-infiltrating T cells by interrupting mitophagy. This causes a metabolic crisis for the infiltrating T cells in sustaining their metabolic fitness and flexibility. Furthermore, we hypothesize that declined mitochondria-derived retrograde signals resulted from mitochondrial dysfunction may lead to T cell dysfunction/exhaustion and altered immune responses through epigenetic reprogramming and altered proteome-metabolic regulatory circuits. The objectives of this proposal are to delineate how tumor cells influence the mitochondrial dynamics of T cells and define the unexplored immunometabolic regulations of T cell functions that are controlled by mitochondria. Lastly, we aim to new methods to restore missing retrograde signals in T cells, which could allow them to prevent mitochondrial dysfunction-induced epigenetic and transcriptomic changes. This work represents an entirely new perspective on control of T cell functions by the immunosuppressive tumor microenvironment, and it may reveal new dimensions of immunometabolic regulation.
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Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
1015 LAUSANNE
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