Descripción del proyecto
Descubrir nuevas dimensiones de la regulación inmunometabólica
Cuando las células inmunitarias se activan adecuadamente, las investigaciones demuestran que los linfocitos T reactivos a tumores y otros tipos de células inmunitarias pueden destruir los tumores. Se trata de un gran avance en el tratamiento oncológico. El proyecto MitoGuide, financiado con fondos europeos, se centrará en cómo el restablecimiento de la aptitud metabólica de los linfocitos T representa una estrategia que podría reforzar la inmunidad antineoplásica. El éxito de esta estrategia depende de nuestra comprensión de los mecanismos subyacentes utilizados por las células tumorales para abolir la aptitud metabólica de los linfocitos T, y de cómo la programación metabólica controla las funciones de estos linfocitos T. El equipo del proyecto dilucidará cómo las células tumorales influyen en la dinámica mitocondrial de los linfocitos T y definirá las regulaciones inmunometabólicas desconocidas de las funciones de los linfocitos T controladas por las mitocondrias.
Objetivo
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.
Ámbito científico
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Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
1015 LAUSANNE
Suiza