Breaking oncometabolites dynamics for next-generation dendritic cells tumor immunotherapy

Descripción del proyecto

Dinámica de oncometabolitos para el tratamiento avanzado de tumores con células dendríticas

La inmunoterapia aprovecha el sistema inmunitario del organismo para combatir el cáncer, destacando el papel del microambiente tumoral (MAT) en la configuración de las respuestas inmunitarias. La manipulación de los metabolitos derivados de los tumores, conocidos como oncometabolitos, puede reforzar la inmunidad antitumoral. En las investigaciones se demuestra que la supresión del receptor de hidrocarburos arílicos (AhR) en las células presentadoras de antígenos puede desencadenar el rechazo tumoral, lo que sugiere que el AhR detecta la composición del MAT y regula la actividad inmunitaria. El equipo del proyecto REACT-DC, financiado por el CEI, pretende identificar metabolitos en el MAT que activen el AhR e investigar su papel en el rechazo tumoral. También desarrollará estrategias para inhibir el AhR o sus vías descendentes en células presentadoras de antígenos seleccionadas mediante el análisis unicelular, la edición de genes y la química computacional, con el objetivo de descubrir dianas terapéuticas y evitar la fuga tumoral.

Objetivo

"Owing to an increased appreciation of the potential for immunotherapy in neoplasia, much attention has been focuing on a greater understanding of the immune, bidirectional intricacies involving the Tumor MicroEnvironment (TME). Recent work has demonstrated that TME elicits environmental changes, metabolic in nature, in the host’s immune cells, that dampen their ability to REACT against tumors. Manipulating the biology of oncometabolites can strengthen an antitumor immune response as well as circumvent therapy resistance. Here I propose innovative modalities to tackle this problem. The Aryl hydrocarbon Receptor (AhR), best known as the receptor for dioxins, has recently been shown to be one ""central node"" for communication between host's cells and its ligands, disparate as the nature and source. I have recently found that selective AhR deletion in a subset of antigen presenting cells triggers the rejection of an otherwise progressive fibrosarcoma tumor in vivo. I thus hypothesize that, AhR, expressed in orchestrators of immune responsiveness, represents a key sensor of TME composition, influencing the outcome of an immune reaction against tumors. The main objective of this project is to identify AhR-activating metabolites in TME and disclose their impact on tumor rejection or progression. In parallel, I aim at developing novel advanced strategies, with a high degree of translatability to human cells, to specifically inhibit AhR or AhR-dependent programs in selected APCs. I will combine state-of-the-art technology with new and powerful technologies, including advanced single-cell analysis, promoter gene-editing approaches and computational chemistry. The potential of such a project is very high, because such metabolites may be predictors of immune activation or suppression in TME, and the downstream targets of those immunesuppressive oncometabiltes may represent druggable targets to inhibit tumor escape mechanisms."