TY - JOUR
T1 - Macrophages are metabolically heterogeneous within the tumor microenvironment
AU - Geeraerts, Xenia
AU - Fernández-Garcia, Juan
AU - Hartmann, Felix J.
AU - de Goede, Kyra E.
AU - Martens, Liesbet
AU - Elkrim, Yvon
AU - Debraekeleer, Ayla
AU - Stijlemans, Benoit
AU - Vandekeere, Anke
AU - Rinaldi, Gianmarco
AU - De Rycke, Riet
AU - Planque, Mélanie
AU - Broekaert, Dorien
AU - Meinster, Elisa
AU - Clappaert, Emile
AU - Bardet, Pauline
AU - Murgaski, Aleksandar
AU - Gysemans, Conny
AU - Nana, Frank Aboubakar
AU - Saeys, Yvan
AU - Bendall, Sean C.
AU - Laoui, Damya
AU - Van den Bossche, Jan
AU - Fendt, Sarah Maria
AU - Van Ginderachter, Jo A.
N1 - Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2021/12/28
Y1 - 2021/12/28
N2 - Macrophages are often prominently present in the tumor microenvironment, where distinct macrophage populations can differentially affect tumor progression. Although metabolism influences macrophage function, studies on the metabolic characteristics of ex vivo tumor-associated macrophage (TAM) subsets are rather limited. Using transcriptomic and metabolic analyses, we now reveal that pro-inflammatory major histocompatibility complex (MHC)-IIhi TAMs display a hampered tricarboxylic acid (TCA) cycle, while reparative MHC-IIlo TAMs show higher oxidative and glycolytic metabolism. Although both TAM subsets rapidly exchange lactate in high-lactate conditions, only MHC-IIlo TAMs use lactate as an additional carbon source. Accordingly, lactate supports the oxidative metabolism in MHC-IIlo TAMs, while it decreases the metabolic activity of MHC-IIhi TAMs. Lactate subtly affects the transcriptome of MHC-IIlo TAMs, increases L-arginine metabolism, and enhances the T cell suppressive capacity of these TAMs. Overall, our data uncover the metabolic intricacies of distinct TAM subsets and identify lactate as a carbon source and metabolic and functional regulator of TAMs.
AB - Macrophages are often prominently present in the tumor microenvironment, where distinct macrophage populations can differentially affect tumor progression. Although metabolism influences macrophage function, studies on the metabolic characteristics of ex vivo tumor-associated macrophage (TAM) subsets are rather limited. Using transcriptomic and metabolic analyses, we now reveal that pro-inflammatory major histocompatibility complex (MHC)-IIhi TAMs display a hampered tricarboxylic acid (TCA) cycle, while reparative MHC-IIlo TAMs show higher oxidative and glycolytic metabolism. Although both TAM subsets rapidly exchange lactate in high-lactate conditions, only MHC-IIlo TAMs use lactate as an additional carbon source. Accordingly, lactate supports the oxidative metabolism in MHC-IIlo TAMs, while it decreases the metabolic activity of MHC-IIhi TAMs. Lactate subtly affects the transcriptome of MHC-IIlo TAMs, increases L-arginine metabolism, and enhances the T cell suppressive capacity of these TAMs. Overall, our data uncover the metabolic intricacies of distinct TAM subsets and identify lactate as a carbon source and metabolic and functional regulator of TAMs.
KW - immunometabolism
KW - immunosuppression
KW - lactate
KW - macrophage metabolism
KW - metabolomics
KW - non-small-cell lung carcinoma
KW - single-cell metabolic profiling
KW - TCA cycle break
KW - tumor microenvironment
KW - tumor-associated macrophages
UR - http://www.scopus.com/inward/record.url?scp=85121698675&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2021.110171
DO - 10.1016/j.celrep.2021.110171
M3 - Article
C2 - 34965415
AN - SCOPUS:85121698675
VL - 37
SP - 110171
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 13
M1 - 110171
ER -