Metabolic program of OX40-driven Treg expansion in cancer: role of iron capture.

Proponente Silvia Piconese - Professore Associato
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Componente Categoria
Sergio Morelli Componenti il gruppo di ricerca
Alessio Grimaldi Dottorando/Assegnista/Specializzando componente il gruppo di ricerca
Componente Qualifica Struttura Categoria
Gian Luca Grazi Direttore UOC Chirurgia Epato-Bilio-Pancreatica, Istituto Nazionale Tumori Regina Elena, Roma Altro personale Sapienza o esterni
Massimo Rossi Professore Ordinario Chirurgia Generale e Specialistica "P. Stefanini", Sapienza Università di Roma Altro personale Sapienza o esterni
Claudio Tripodo Professore Associato Scienze Promozione Salute e Materno Infantile "G. D'Alessandro", Università di Palermo Altro personale Sapienza o esterni

The local accumulation of Tregs, highly expressing the costimulatory receptor OX40 and displaying a stable and activated phenotype, contributes to maintain immunosuppression in hepatic cirrhosis and hepatocellular carcinoma microenvironments. In these contexts, our preliminary data highlight a connection between OX40 signal and specific metabolic routes, namely glycolysis, cholesterol/lipid biosynthesis, and iron/transferrin capture.
We hypothesize that OX40 orchestrates a metabolic program of Treg expansion and suppression, based on the effects of extracellular iron sequestration from effector cells. Our main aim will be to demonstrate that iron scavenging mediates OX40+ Treg suppressive function thus promoting tumor progression.
The impact of iron/transferrin uptake on Treg proliferation and suppression will be assessed, in relation to OX40 expression and engagement, by multiple techniques (multicolor flow cytometry, microscopy, biochemical and functional assays), in three settings: in vitro, using stimulated human Tregs; ex vivo, analyzing hepatic Tregs from hepatocellular carcinoma patients with variable iron homeostasis perturbations; in vivo, monitoring Tregs and tumor growth in mouse models of high fat choline-deficient diet-induced, or transplanted, hepatocellular carcinoma, combined with the Treg-restricted genetic deletion of transferrin receptor.
We expect to delineate a previously unrecognized mechanism of Treg suppression, based on iron sequestration from the microenvironment: this event may become especially relevant in tumor-infiltrating OX40+ Tregs and may thus represent new targets for more focused immunotherapies.


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