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) 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.