Project description
Uncovering new dimensions of immunometabolic regulation
When immune cells are properly activated, research shows that tumour-reactive T cells and other immune cell types can destroy tumours. This is a major breakthrough in cancer treatment. The EU-funded MitoGuide project will focus on how restoring the metabolic fitness of T cells represents a promising strategy for strengthening anti-tumour immunity. Success of this strategy hinges on our understanding of the underlying mechanisms utilised by tumour cells to abolish the metabolic fitness of T cells, and of how metabolic programming controls T cell functions. The project will elucidate how tumour cells influence the mitochondrial dynamics of T cells and define the unexplored immunometabolic regulations of T cell functions that are controlled by mitochondria.
Objective
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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Funding Scheme
ERC-STG - Starting GrantHost institution
1015 LAUSANNE
Switzerland