Projektbeschreibung
Kaperung des Stoffwechsels von Immunzellen durch Tumoren
Trotz ihres großen Potenzials hat sich die Immuntherapie in der klinischen Praxis nur für einen Bruchteil der Menschen mit Krebs als nützlich erwiesen. Um die klinischen Ergebnisse zu verbessern, sind neuartige Ansätze erforderlich. Der Schwerpunkt des vom Europäischen Forschungsrat finanzierten Projekts SpatialTMEMetabolism wird auf dem Stoffwechsel menschlicher Immunzellen liegen. Die Forschenden gehen von der Hypothese aus, dass Tumoren bestimmte metabolische Nischen schaffen, um Immunreaktionen zu unterdrücken. Sie werden mithilfe der Erstellung von Einzelzell-Stoffwechselprofilen herausfinden, wie verschiedene Krebsarten den Stoffwechsel der Immunzellen beeinflussen, und voraussagbare Immunzellzustände für das Ansprechen auf eine Immuntherapie identifizieren. Die Arbeit wird zur Identifizierung neuer molekularer Ziele führen, die therapeutisch genutzt werden können.
Ziel
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.
Wissenschaftliches Gebiet
- 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
Schlüsselbegriffe
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-ERC - HORIZON ERC GrantsGastgebende Einrichtung
69120 Heidelberg
Deutschland