Descrizione del progetto
Dirottamento metabolico delle cellule immunitarie da parte dei tumori
Nonostante le sue grandi promesse, nella pratica clinica l’immunoterapia si è dimostrata utile solo per una frazione dei pazienti oncologici. Sono necessari nuovi approcci per migliorare i risultati clinici. Il progetto SpatialTMEMetabolism, finanziato dal Consiglio europeo della ricerca, si concentrerà sul metabolismo delle cellule immunitarie umane. I ricercatori lavoreranno secondo l’ipotesi che i tumori creino nicchie metaboliche definite per sopprimere le risposte immunitarie. Utilizzando la profilazione metabolica di una singola cellula, i ricercatori scopriranno come i diversi tipi di cancro influenzano il metabolismo delle cellule immunitarie e identificheranno gli stati delle cellule immunitarie predittivi della risposta all’immunoterapia. Il lavoro porterà all’identificazione di nuovi bersagli molecolari che possono essere sfruttati a livello terapeutico.
Obiettivo
The success of cancer immunotherapy, especially immune checkpoint inhibition (ICI), demonstrates the ability of the immune system to fight tumors. However, only a fraction of patients benefit from currently available therapies, and we need to find novel approaches to improve clinical responses. Cellular metabolism has emerged as a key determinant of multiple aspects of immune cell function, especially T cell exhaustion and anti-inflammatory macrophage polarization. However, we currently do not have a good understanding of the metabolic states of human immune cells since no technology has been available to quantify them directly in clinical tumor tissues.
I hypothesize that tumors create spatially defined metabolic environments, also called metabolic niches, to suppress immune cells and that this mechanism can be targeted to improve cancer immunotherapy. To test this, we will (1) quantify the metabolic states of immune cells in solid human cancers, (2) identify metabolic immune cell states that predict response to ICI, and (3) reveal the mechanism of metabolic niche formation in tumor organoids. We will quantify cellular metabolism and phenotype directly in human tumor tissues, using the innovative single-cell metabolic profiling (scMEP) approach I have recently developed. We will combine this with multiplexed ion beam imaging (MIBI), a technology that enables 40-dimensional proteomic imaging. MIBI imaging will be complemented by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and machine learning frameworks for the analysis of these multi-omic datasets.
Taken together, this project will uncover generalizable concepts of how different tumor entities influence the cellular metabolism of immune cells to modulate their function. The potential therapeutic targets that will emerge from this analysis could thus contribute to improved treatment options for various types of human cancer.
Campo scientifico
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
- natural sciencescomputer and information sciencesartificial intelligencemachine learning
- natural sciencesphysical sciencesopticslaser physics
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
69120 Heidelberg
Germania