Branched-chain ketoacids derived from cancer cells modulate macrophage polarization and metabolic reprogramming

Author(s)
Zhengnan Cai, Wan Li, Martin Brenner, Sheyda Bahiraii, Elke H Heiss, Wolfram Weckwerth
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.

Organisation(s)
Functional and Evolutionary Ecology, Department of Pharmaceutical Sciences
External organisation(s)
University of Vienna
Journal
Frontiers in Immunology
Volume
13
No. of pages
14
ISSN
1664-3224
DOI
https://doi.org/10.3389/fimmu.2022.966158
Publication date
10-2022
Peer reviewed
Yes
Austrian Fields of Science 2012
301209 Pharmacy
Keywords
ASJC Scopus subject areas
Immunology and Allergy, Immunology
Sustainable Development Goals
SDG 3 - Good Health and Well-being
Portal url
https://ucrisportal.univie.ac.at/en/publications/3ed124be-6cf0-4ee2-ab5f-03d9d32fe983