Title
Branched-chain ketoacids derived from cancer cells modulate macrophage polarization and metabolic reprogramming
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Abstract
Macrophages are prominent immune cells in the tumor microenvironment that can be educated into pro-tumoral phenotype by tumor cells to favor tumor growth and metastasis. The mechanisms that mediate a mutualistic relationship between tumor cells and macrophages remain poorly characterized. Here, we have shown in vitro that different human and murine cancer cell lines release branched-chain α-ketoacids (BCKAs) into the extracellular milieu, which influence macrophage polarization in an monocarboxylate transporter 1 (MCT1)-dependent manner. We found that α-ketoisocaproate (KIC) and α-keto-β-methylvalerate (KMV) induced a pro-tumoral macrophage state, whereas α-ketoisovalerate (KIV) exerted a pro-inflammatory effect on macrophages. This process was further investigated by a combined metabolomics/proteomics platform. Uptake of KMV and KIC fueled macrophage tricarboxylic acid (TCA) cycle intermediates and increased polyamine metabolism. Proteomic and pathway analyses revealed that the three BCKAs, especially KMV, exhibited divergent effects on the inflammatory signal pathways, phagocytosis, apoptosis and redox balance. These findings uncover cancer-derived BCKAs as novel determinants for macrophage polarization with potential to be selectively exploited for optimizing antitumor immune responses.
Keywords
macrophage polarizationtumor-associated macrophagespanomicsBCKAs Fc-gamma receptor (FCgR)-mediated phagocytosistumor necrosis factor alpha (TNFα)-nuclear factor kappa B (NFκB) -mediated inflammatory pathwayapoptosis
Object type
Language
English [eng]
Persistent identifier
https://phaidra.univie.ac.at/o:1641767
Appeared in
Title
Frontiers in Immunology
Volume
13
ISSN
1664-3224
Issued
2022
Publisher
Frontiers Media SA
Date issued
2022
Access rights
Rights statement
© 2022 Cai, Li, Brenner, Bahiraii, Heiss and Weckwerth
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