Epigenetic manipulation of DC-donated mitochondria boots T cell anti-tumour immunity

The inability of endogenous and synthetic T cells to eliminate cancer cells has been largely linked to mitochondrial dysfunction. Conversely, metabolic reprogramming of CD8 T cells may escalate anti-tumour immune responses.

Under immunostimulatory conditions, dendritic cells (DCs) can initiate an antigen-specific T cell immune response. As CD28 contributes to T cell mitochondrial priming, it is conceivable that DC-co-stimulation can also promote T cell mitochondrial function. Since a recent study has shown that bone marrow stroma cells can transfer their mitochondria to boost CD8 T cell function in vitro, we infer that DCs may exert a similar function both in vitro and in vivo.

Taking into account that mitochondrial DNA (mtDNA) serves as the building brick, we seek to investigate how it is epigenetically regulated following mitochondria transfer.

1. To demonstrate that DC co-stimulation increases T cell metabolic fitness partially through mitochondrial donation;
2. To explore whether 6mA methylation selectively restricts donor mtDNA transcription in mitochondria-transferred CD8 T cells;
3. To understand how 6mA methyltransferase METTL4 impedes DC-induced CD8 T cell fitness;
4. To examine whether METTL4 depletion enhances adoptive T cell therapy.

1. DC-CD8 T cell co-stimulation system;
2. Mitochondrial reporter system;
3. DC-co-stimulation mouse tumour models;
4. Adoptive T cell therapy models.

1. Mitochondrial transfer recognised as part of DC-T cell co-stimulation;
2. Understanding T cell epigenetics in a mtDNA level;
3. Combining mitochondrial supercharge and epigenetic reprograming to improve T cell therapy.