Exploiting fundamental insights of m6A methylation on CD8 T cell differentiation and function to boost medicinal T cell products

Adoptive T cell therapies have revolutionised cancer treatment in some haematological tumours.

Despite astounding advances, patients often relapse because the transferred T cells have low persistence and they lose their effector function against cancer cells.

The prime challenge for improving T cell therapies is to decipher the mechanisms that define T cell effector function and memory formation.

The MA6TCELL project aims to disentangle this problem by defining how m6A methylation on mRNA regulates human CD8 T cell differentiation and function. m6A is the most abundant mRNA methylation and determines gene expression by regulating mRNA metabolism, altering as such cell function.

Using the miCLIP assay, I previously mapped genome-wide the m6A sites on the mRNAs of human CD8 T cells (unpublished data I will provide the host with). This map revealed that m6A occurs not only at the known DRACH sequences, but also at AU-rich sequences (AREs).

Intriguingly, the host has uncovered that AREs are critical regulators of cytokine production in memory CD8 T cells (host expertise).

My pilot experiments revealed that chemical inhibition of a m6A demethylase in CD8 T cells decreased cytokine production, further supporting my hypothesis that m6A methylation controls CD8 T cell differentiation and function.

To test this hypothesis the M6ATCELL project will: 1) define the regulatory mechanisms of m6A methylation in human CD8 T cell differentiation and effector function and 2) test whether m6A enzyme inhibitors improve the potency of CD8 T cell therapies using chimeric antigen receptor (CAR) T cells.

Our findings will yield fundamental insights in T cell biology, which can be relevant for multiple adoptive T cell therapies. My long-term aim is to transfer my scientific findings from bench-to-bedside.

Thus, I also secured a placement at the European Medicines Agency and if this proposal is granted, I will be trained on the regulatory guidelines of medicinal T cell products.