DICE

There is emerging evidence that Western diet-derived metabolites induce reprogramming of circulating immune cells, leading to a long-lasting pro-inflammatory phenotype, termed trained immunity, which may be the trigger for many pathologies, including cancer. Western dietary habits are associated with perturbations of systemic myeloid compartment, including Myeloid-Derived Suppressor cells (MDSCs), which impair antitumour immunity and limit the efficacy of some immunotherapies. Hence, there is an urgent need for strategies that can restore long-term immune control of cancer. The key mechanisms underlying these immunological events involve intracellular metabolism and epigenetic reprogramming, although the latter remains partially unexplored. This project aims to untangle the epigenomic impact of dietary intervention (namely anti-inflammatory diet, AID) for the identification of new epigenetic therapeutic targets able to reverse trained immunity and restore antitumour responses. We hypothesise that AID may reduce pro-inflammatory pathways and immune suppression in cancer. Thus, dissecting the epigenomic mechanisms mediating the immunological impact of AID would reveal ground-breaking information on dietary interventions as a strategy to promote epigenetic reprogramming to reverse immune dysfunctions in cancer.
The aim of the proposal is to unravel the epigenetic determinants mediating the immune effects of AID at the systemic level and at the tumour site, in patients with early stages of cancer. Primary aims: to analyse in the clinical setting AID-mediated modulation of immune cell profile and investigate the underlying epigenomic mechanisms in depth by sensitive and novel multiomic approaches. Secondary aim: to identify and evaluate novel epigenetic biomarkers and targets with translational potential. We will investigate epigenomic mechanisms of AID-induced immune modulation in the clinical setting, i.e. the effect AID before and after surgical removal of primary tumour in patients with early stage breast and colorectal cancer. We will use a comprehensive integration of multiomics data between different levels of epigenetic regulation (DNA methylation, gene expression and chromatin organization) to identify novel clinically relevant biomarkers and potential druggable targets.
Expected results and potential impact: generating knowledge on the epigenomic effects of pre- and post-surgery AID and on their potentiating effects on reducing trained immunity. Improving cancer prevention (dietary intervention) and treatment strategies (use of existing epigenetic drugs and immunotherapies) to increase survival rates and quality of life of cancer patients. Integration of new knowledge into pharmaceutical/industrial applications (development of new epigenetic drugs). Creating networking infrastructures and databases, sharing of data and knowledge. Streamlining research priorities and research needs at European level.