H2020Индивидуална стипендия2023–2025

EnhancemenT · Enhancing cytotoxic T-lymphocyte tumour-fighting capacity through the modulation of metabolic pathways regulated by ZFP36/ZFP36L1 RNA-binding proteins

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2023-03-01 → 2025-02-28
Финансиране от ЕС: 212 934 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Протеините от семейството ZFP36 регулират метаболизма и епигенетиката на Т-лимфоцитите, които атакуват раковите клетки. Разбирането на тези процеси помага за подобряване на имунотерапията при рак и лечението на хронични инфекции.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Enhancing cytotoxic T-lymphocyte tumour-fighting capacity through the modulation of metabolic pathways regulated by ZFP36/ZFP36L1 RNA-binding proteins

Cytotoxic CD8+ T-lymphocytes (CTLs) are a type of immune cell specialised in recognising and killing infected and tumour cells. This ability to kill cancer cells is also exploited in T-lymphocyte-based immunotherapies using chimeric antigen receptor (CAR) T-cells, where these cells are genetically engineered and transferred into the patient to potentiate their anti-tumour immune response. CTLs are generated upon a process in which naïve T-lymphocytes recognise a specific “foreign” protein from a tumour or a virus, start proliferating, and differentiate into a cohort of effector T-lymphocytes which maintain specificity for the same foreign protein. However, CTLs are often limited upon long-term exposure to viral or cancer molecules and eventually fail in defeating the disease. Therefore, there is need to discover new strategies to potentiate CTL survival and effector functions in chronic infections and cancer, also to improve T-lymphocyte-based immunotherapies. My project aimed at identifying new molecular pathways that control T-lymphocyte activation and effector functions. I focused on the role of specific RNA-binding proteins belonging to the ZFP36-family. I discovered that beyond regulating the production of specific effector molecules in T-lymphocytes, ZFP36-family proteins also regulate RNAs encoding epigenetic and metabolic factors, ultimately affecting T-lymphocyte epigenetics. By epigenetics we refer to all those processes that regulate the activation or repression of a gene at the DNA level, without changing the DNA sequence. Therefore, my work laid the basis for the identification of new molecular pathways that may be targeted to improve success of cancer immunotherapy and develop innovative treatments for chronic infections, both very urgently needed.

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

Цел на проекта

Cytotoxic CD8+ T-lymphocytes (CTLs) recognize and kill infected and malignant cells. Although CTLs recognize tumour-specific antigens, they often fail to limit cancer growth, as the cancer micro-environment rapidly suppresses their functionality. Therefore, there is the need to unveil new molecular circuits controlling CTL activation, the process through which T-cells proliferate and differentiate into an antigen-specific subpopulation with effector functions. In this way it will be possible to enhance CTL tumour-fighting capacity and improve the efficacy of immunotherapies, especially against solid cancers. My project will focus on how post-transcriptional regulation of metabolism modulates CTL activation. Post-transcriptional responses are fast and important for adaptation to rapidly changing environments. RNA-binding proteins (RBPs) are fundamental modulators of post-transcriptional regulation of many cellular processes, but less is known about how they regulate metabolism. By combining multi-omics approaches (i.e. proteomics, transcriptomics, metabolomics and in-vivo experiments) I will investigate how metabolic pathways in CTLs are modulated by specific RBPs. I will study how these RBPs regulate the stability and the translation of mRNAs encoding metabolic enzymes. Finally, I will control the expression of these RBPs in CAR-T cells (engineered T-lymphocytes used in cancer immunotherapies) to regulate metabolic pathways and enhance the in-vivo solid tumour-fighting capacity of these cells. Thus, my research will lay the groundwork for the identification of new methods to stimulate metabolism of tumour-infiltrating CTLs to enhance their functionality. My expertise in RNA-biology will complement the new skills I will learn from my host lab and collaborators, combining diverse disciplines to investigate fundamental immunological questions and apply my findings to in-vivo cancer immunotherapy.

Оригинален текст от CORDIS (на английски).

Участници

THE BABRAHAM INSTITUTE · CambridgeКоординаторОбединеното кралство