Metabolic reprogramming of hypoxic tumor-associated macrophages through CSF-1R targeting favors treatment efficiency in colorectal cancers

• Published in: Journal for immunotherapy of cancer 2024-09, Vol.12 (9), p.e009602
• Main Authors: Gharzeddine, Khaldoun, Gonzalez Prieto, Cristina, Malier, Marie, Hennot, Clara, Grespan, Renata, Yamaryo-Botté, Yoshiki, Botté, Cyrille Y, Thomas, Fabienne, Laverriere, Marie-Hélène, Girard, Edouard, Roth, Gael, Millet, Arnaud
• Format: Article
• Language: English
• Subjects: Amino acids; Basic Tumor Immunology; Cell culture; Chemotherapy; Cholesterol; Colorectal Cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Dehydrogenases; Fatty acids; Flow cytometry; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Genes; Humans; Hypoxia; Kinases; Life Sciences; Lipids; Macrophage; Medical prognosis; Metabolic Reprogramming; Metabolism; Metabolites; Original Research; Proteins; Receptor, Macrophage Colony-Stimulating Factor - metabolism; Transcription factors; Tumor microenvironment - TME; Tumor-Associated Macrophages - metabolism
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2024-009602

BackgroundTumor-associated macrophages participate in the complex network of support that favors tumor growth. Among the various strategies that have been developed to target these cells, the blockade of the colony-stimulating factor 1 receptor (CSF-1R) receptor is one of the most promising ones. Here, we characterize the resulting state of human macrophages exposed to a CSF-1R kinase inhibitor.MethodsUsing RNA sequencing and metabolomics approach, we characterize the reprogramming of human monocyte-derived macrophages under CSF-1R targeting.ResultsWe find that CSF-1R receptor inhibition in human macrophages is able to impair cholesterol synthesis, fatty acid metabolism and hypoxia-driven expression of dihydropyrimidine dehydrogenase, an enzyme responsible for the 5-fluorouracil macrophage-mediated chemoresistance. We show that this inhibition of the CSF-1R receptor leads to a downregulation of the expression of sterol regulatory element-binding protein 2, a transcription factor that controls cholesterol and fatty acid synthesis. We also show that the inhibition of extracellular signal-regulated kinase 1/2 phosphorylation resulting from targeting the CSF-1R receptor destabilizes the expression of hypoxic induced factor 2 alpha in hypoxia resulting in the downregulation of dihydropyrimidine dehydrogenase expression restoring the sensitivity to 5-fluorouracil in colorectal cancer.ConclusionsThese results reveal the unexpected metabolic rewiring resulting from the CSF-1R receptor targeting of human macrophages and its potential to reverse macrophage-mediated chemoresistance in colorectal tumors.