HEИндивидуална стипендия2023–2025

M6ATCELL · Exploiting fundamental insights of m6A methylation on CD8 T cell differentiation and function to boost medicinal T cell products

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период: 2023-04-01 → 2025-09-30
Финансиране от ЕС: 234 530 €
Участници: 2
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Химичната модификация m6A на РНК влияе върху това как Т-клетките се развиват и произвеждат молекули за атака срещу ракови клетки. Разбирането на този процес може да помогне за подобряване на имунните терапии при лечението на рак.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

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

The immune system relies on tightly regulated gene expression to mount effective responses to infections and cancer. One of the key regulators of gene expression is a chemical modification known as N6-methyladenosine (m6A), which is added to messenger RNA (mRNA) and can influence its stability, translation, and ultimately, protein production. Although m6A has emerged as a major player in many biological processes, its role in human CD8+ T cells—the immune cells responsible for directly killing infected or cancerous cells—has remained largely unexplored. This project aimed to fill that gap by systematically investigating how m6A methylation affects the function and therapeutic potential of CD8+ T cells. The research focused on four main scientific objectives: 1) To define how m6A methylation modulates the production of effector molecules (such as cytokines) that CD8+ T cells use to attack virally infected and cancerous cells. 2) To determine the role of m6A methylation in CD8+ T cell differentiation, a process through which T cells become specialised to perform distinct immune functions. 3) To identify chemical inhibitors that can modulate m6A methylation in CD8+ T cells 4) To assess whether targeting m6A enzymes with chemical inhibitors could improve the function of T cells used in cancer immunotherapy. The broader vision of the project was to explore whether manipulating RNA modifications with chemical inhibition could serve as a new strategy to enhance immune responses and optimise cell therapies. By focusing on both basic mechanisms and translational potential, this research bridged molecular biology with clinical innovation, particularly in the context of cancer immunotherapy.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

Stichting Sanquin Bloedvoorziening · AmsterdamКоординаторНидерландия
THE EUROPEAN MEDICINES AGENCY · AmsterdamНидерландия