Project description
RNA-binding proteins as the modulators of cytotoxic T lymphocyte tumour-fighting efficacy
Cytotoxic CD8+ T lymphocytes (CTLs) recognise tumour-specific antigens and kill malignant cells. However, CTLs often fail to limit cancer growth as the result of their functionality suppression from the tumour microenvironment. Understanding molecular circuits controlling CTL activation will open the possibility to enhance CTL tumour-fighting capacity and the efficacy of immunotherapies. Funded by the Marie Skłodowska-Curie Actions programme, the EnhancemenT project will study the post transcriptional regulation of metabolism to modulate CTL activation. The project will focus on the RNA-binding proteins as the fundamental modulators of post-transcriptional regulation of metabolism, creating a platform for the identification of new methods to stimulate the metabolism and functionality of tumour-infiltrating CTLs.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
CB22 3AT Cambridge
United Kingdom