Summary
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 Using the miCLIP assay, I previously mapped genome-wide the m6A sites on the mRNAs of human CD8 T cells (unpublished data I will provide the host with).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.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/101107176 |
| Start date: | 01-04-2023 |
| End date: | 30-09-2025 |
| Total budget - Public funding: | - 234 530,00 Euro |
Cordis data
Original description
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.Status
SIGNEDCall topic
HORIZON-MSCA-2022-PF-01-01Update Date
31-07-2023
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