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

Projektbeschreibung

RNA-bindende Proteine als Modulatoren der tumorbekämpfenden Wirkung von zytotoxischen T-Lymphozyten

CD8-positive zytotoxische T-Lymphozyten (ZTL) erkennen tumorspezifische Antigene und töten bösartige Zellen ab. ZTL sind jedoch oft nicht in der Lage, das Krebswachstum einzuschränken, da ihre Funktionalität durch die Mikroumgebung des Tumors unterdrückt wird. Ein genaueres Verständnis von den molekularen Schaltkreisen, welche die ZTL-Aktivierung steuern, wird es potenziell ermöglichen, die tumorbekämpfenden Eigenschaften von ZTL und die Wirkung von Immuntherapien zu verstärken. Das im Rahmen der Marie-Skłodowska-Curie-Maßnahmen finanzierte Projekt EnhancemenT wird untersuchen, wie die posttranskriptionelle Regulation des Stoffwechsels die ZTL-Aktivierung moduliert. Der Schwerpunkt der Forschenden liegt auf den RNA-bindenden Proteinen und ihrer Funktion als grundlegende Modulatoren der posttranskriptionellen Stoffwechselregulation. Letztlich soll die Arbeit eine Plattform hervorbringen, um neue Methoden zur Anregung des Stoffwechsels und der Funktionalität von tumorinfiltrierenden ZTL zu identifizieren.

Ziel

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.