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

Descripción del proyecto

Las proteínas de unión al ARN: moduladores de la eficacia antitumoral de los linfocitos T citotóxicos

Los linfocitos T citotóxicos (LTC) CD8+ reconocen antígenos específicos para tumores y matan las células malignas. Sin embargo, los LTC a menudo son incapaces de limitar la neoplasia maligna porque el microentorno tumoral suprime su funcionalidad. El conocimiento de los circuitos moleculares que controlan la activación de los LTC permitirá mejorar la capacidad antitumoral de los LTC y la eficacia de las inmunoterapias. El equipo del proyecto EnhancemenT, financiado por las Acciones Marie Skłodowska-Curie, estudiará la regulación postranscripcional del metabolismo para modular la activación de los LTC. El proyecto se centrará en las proteínas de unión al ARN como moduladores fundamentales de la regulación postranscripcional del metabolismo y creará una plataforma para identificar nuevos métodos que estimulen el metabolismo y la funcionalidad de los LTC que se infiltran en los tumores.

Objetivo

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.