Background
Optimising mitochondrial fitness is crucial for both endogenous anti-tumour T cells and engineered T cell therapy products. Dendritic cells (DCs) play a pivotal role in orchestrating T cell immune responses; however, it is unclear whether DCs can modulate T cell mitochondrial function and whether this cellular interaction can be harnessed in T cell therapy.
Notably, intercellular mitochondria transfer represents an emerging mechanism in cancer immunobiology, with the potential to enhance T cell therapy efficacy. We preliminarily observed DC-donated mitochondria in co-stimulated CD8 T cells in vitro and hypothesise that this phenomenon also exists in vivo. Since mitochondrial DNA (mtDNA) plays a key role in metabolic fitness, we will investigate its epigenetic regulation following mitochondria transfer.
Our preliminary data suggests that aberrant expression of the mtDNA methyltransferase METTL4 impairs DC co-stimulation of CD8 T cells. Therefore, we aim to explore how mtDNA methylation and transcription are regulated in mitochondria-transferred T cells and whether METTL4 depletion can rewire this process to reserve T cell stemness and responsiveness.
Aim
- Demonstrate the importance of DC mitochondria donation in T cell anti-tumour immunity;
- Explore whether 6mA methylation selectively restricts donor mtDNA transcription in mitochondria-transferred CD8 T cells
- Identify how 6mA methyltransferase METTL4 impedes DC-induced CD8 T cell fitness;
- Enhance adoptive T cell therapy by targeting the METTL4-6mA machinery.
Approach
- In vitro T cell activation/exhaustion systems;
- In vitro and in vivo mitochondrial reporter systems;
- Chemoimmunotherapy models;
- Adoptive T cell therapy models.
Project Potential
The mitochondria transfer phenomenon is paradigm-shifting our understanding of cancer immunobiology. With DC-T cell communication interpreted at the intercellular mtDNA level, this study will update and translate our knowledge about how T cells acquire mitochondrial fitness and treatment responsiveness. By combining mitochondrial supercharging with epigenetic reprogramming, we may develop better T cell therapy products against a wide range of cancers and treatment responsiveness. By combining mitochondrial supercharging with epigenetic reprogramming, we may develop better T cell therapy products against a wide range of cancers.