Macrophages are metabolically heterogeneous within the tumor microenvironment

Xenia Geeraerts; Juan Fernández-Garcia; Felix J. Hartmann; Kyra E. de Goede; Liesbet Martens; Yvon Elkrim; Ayla Debraekeleer; Benoit Stijlemans; Anke Vandekeere; Gianmarco Rinaldi; Riet De Rycke; Mélanie Planque; Dorien Broekaert; Elisa Meinster; Emile Clappaert; Pauline Bardet; Aleksandar Murgaski; Conny Gysemans; Frank Aboubakar Nana; Yvan Saeys; Sean C. Bendall; Damya Laoui; Jan Van den Bossche; Sarah Maria Fendt; Jo A. Van Ginderachter

doi:https://doi.org/10.1016/j.celrep.2021.110171

Macrophages are metabolically heterogeneous within the tumor microenvironment

Xenia Geeraerts, Juan Fernández-Garcia, Felix J. Hartmann, Kyra E. de Goede, Liesbet Martens, Yvon Elkrim, Ayla Debraekeleer, Benoit Stijlemans, Anke Vandekeere, Gianmarco Rinaldi, Riet De Rycke, Mélanie Planque, Dorien Broekaert, Elisa Meinster, Emile Clappaert, Pauline Bardet, Aleksandar Murgaski, Conny Gysemans, Frank Aboubakar Nana, Yvan SaeysSean C. Bendall, Damya Laoui, Jan Van den Bossche, Sarah Maria Fendt, Jo A. Van Ginderachter

Research output: Contribution to journal › Article › Academic › peer-review

63 Citations (Scopus)

Abstract

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)-II^hi TAMs display a hampered tricarboxylic acid (TCA) cycle, while reparative MHC-II^lo TAMs show higher oxidative and glycolytic metabolism. Although both TAM subsets rapidly exchange lactate in high-lactate conditions, only MHC-II^lo TAMs use lactate as an additional carbon source. Accordingly, lactate supports the oxidative metabolism in MHC-II^lo TAMs, while it decreases the metabolic activity of MHC-II^hi TAMs. Lactate subtly affects the transcriptome of MHC-II^lo 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.

Original language	English
Article number	110171
Journal	Cell reports
Volume	37
Issue number	13
DOIs	https://doi.org/10.1016/j.celrep.2021.110171
Publication status	Published - 28 Dec 2021

Keywords

TCA cycle break
immunometabolism
immunosuppression
lactate
macrophage metabolism
metabolomics
non-small-cell lung carcinoma
single-cell metabolic profiling
tumor microenvironment
tumor-associated macrophages

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https://doi.org/10.1016/j.celrep.2021.110171

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Geeraerts, X., Fernández-Garcia, J., Hartmann, F. J., de Goede, K. E., Martens, L., Elkrim, Y., Debraekeleer, A., Stijlemans, B., Vandekeere, A., Rinaldi, G., De Rycke, R., Planque, M., Broekaert, D., Meinster, E., Clappaert, E., Bardet, P., Murgaski, A., Gysemans, C., Nana, F. A., ... Van Ginderachter, J. A. (2021). Macrophages are metabolically heterogeneous within the tumor microenvironment. Cell reports, 37(13), Article 110171. https://doi.org/10.1016/j.celrep.2021.110171

@article{0ec3ffa4b7e746beb980c78234d8c94e,

title = "Macrophages are metabolically heterogeneous within the tumor microenvironment",

abstract = "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.",

keywords = "TCA cycle break, immunometabolism, immunosuppression, lactate, macrophage metabolism, metabolomics, non-small-cell lung carcinoma, single-cell metabolic profiling, tumor microenvironment, tumor-associated macrophages",

author = "Xenia Geeraerts and Juan Fern{\'a}ndez-Garcia and Hartmann, {Felix J.} and {de Goede}, {Kyra E.} and Liesbet Martens and Yvon Elkrim and Ayla Debraekeleer and Benoit Stijlemans and Anke Vandekeere and Gianmarco Rinaldi and {De Rycke}, Riet and M{\'e}lanie Planque and Dorien Broekaert and Elisa Meinster and Emile Clappaert and Pauline Bardet and Aleksandar Murgaski and Conny Gysemans and Nana, {Frank Aboubakar} and Yvan Saeys and Bendall, {Sean C.} and Damya Laoui and {Van den Bossche}, Jan and Fendt, {Sarah Maria} and {Van Ginderachter}, {Jo A.}",

note = "Funding Information: This work was supported by a PhD fellowship of the Research Foundation ? Flanders (FWO) and a national Belgian fellowship L'Or?al-UNESCO ?For Women in Science? to X.G. J.F.-G. A.V. and G.R. are/were supported by FWO fellowships. J.V.d.B. received a VENI grant from ZonMW (91615052), a Netherlands Heart Foundation Junior Postdoctoral grant (2013T003), a Senior Fellowship (2017T048), and a NWO ENW-KLEIN-1 grant (268). S.-M.F. acknowledges funding from the European Research Council under the ERC Consolidator grant agreement no. 771486?MetaRegulation, FWO Projects, KU Leuven ? FTBO, and Fonds Baillet Latour. J.A.V.G. is supported by grants from Kom op tegen Kanker, Stichting tegen Kanker, and FWO-Vlaanderen. The authors would like to thank Jan Brughmans, Solange Martins, Maryse Schmoetten, Ella Omasta, Marie-Th?r?se Detobel, Nickey Riebeek, Maria Slazak, and Nadia Abou for technical and administrative support. We thank Isabelle Scheyltjens for advice regarding Metascape analysis. Bulk RNA sequencing and analyses were performed by VIB Nucleomics Core (www.nucleomics.be). We thank Benjamin Pavie, Anneke Kremer, and Eef Parthoens from VIB Bioimaging Core-Gent for their support with confocal/electron microscopy analysis and Bart Ghesqui?re from VIB Metabolomics Core. We thank Janick Mathys from VIB for advice regarding statistical analysis. Conceptualization, X.G. J.V.d.B. S.-M.F. and J.A.V.G.; formal analysis, X.G. J.F.-G. F.J.H. K.E.d.G. L.M. A.V. G.R. R.D.R. and M.P.; investigation, X.G. F.J.H. K.E.d.G. Y.E. A.D. B.S. A.V. G.R. R.D.R. D.B. E.M. E.C. P.B. A.M. and C.G.; resources ? provision of patient samples, F.A.N.; writing ? original draft preparation, X.G.; writing ? review & editing: X.G. J.V.d.B. S.-M.F. and J.A.V.G.; visualization: X.G. F.J.H. and L.M.; supervision: Y.S. S.C.B. D.L. J.V.d.B. S.-M.F. and J.A.V.G.; funding acquisition: J.V.d.B. S.-M.F. and J.A.V.G. J.A.V.G. received funding from Precirix, Argenx, and Oncurious for projects unrelated to this manuscript and has functioned as a consultant for MSD and Fund+. S.-M.F. has received funding from Bayer, Merck, and Black Belt Therapeutics for different projects and is on the editorial board of Cell Reports. All other authors declare no competing interests. Funding Information: J.A.V.G. received funding from Precirix, Argenx, and Oncurious for projects unrelated to this manuscript and has functioned as a consultant for MSD and Fund+. S.-M.F. has received funding from Bayer, Merck, and Black Belt Therapeutics for different projects and is on the editorial board of Cell Reports. All other authors declare no competing interests. Funding Information: This work was supported by a PhD fellowship of the Research Foundation – Flanders (FWO) and a national Belgian fellowship L{\textquoteright}Or{\'e}al-UNESCO “For Women in Science” to X.G. J.F.-G., A.V., and G.R. are/were supported by FWO fellowships. J.V.d.B. received a VENI grant from ZonMW ( 91615052 ), a Netherlands Heart Foundation Junior Postdoctoral grant ( 2013T003 ), a Senior Fellowship ( 2017T048 ), and a NWO ENW-KLEIN-1 grant ( 268 ). S.-M.F. acknowledges funding from the European Research Council under the ERC Consolidator grant agreement no. 771486 –MetaRegulation, FWO Projects, KU Leuven – FTBO, and Fonds Baillet Latour. J.A.V.G. is supported by grants from Kom op tegen Kanker, Stichting tegen Kanker, and FWO-Vlaanderen. The authors would like to thank Jan Brughmans, Solange Martins, Maryse Schmoetten, Ella Omasta, Marie-Th{\'e}r{\`e}se Detobel, Nickey Riebeek, Maria Slazak, and Nadia Abou for technical and administrative support. We thank Isabelle Scheyltjens for advice regarding Metascape analysis. Bulk RNA sequencing and analyses were performed by VIB Nucleomics Core ( www.nucleomics.be ). We thank Benjamin Pavie, Anneke Kremer, and Eef Parthoens from VIB Bioimaging Core-Gent for their support with confocal/electron microscopy analysis and Bart Ghesqui{\`e}re from VIB Metabolomics Core. We thank Janick Mathys from VIB for advice regarding statistical analysis. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = dec,

day = "28",

doi = "https://doi.org/10.1016/j.celrep.2021.110171",

language = "English",

volume = "37",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "13",

}

Geeraerts, X, Fernández-Garcia, J, Hartmann, FJ, de Goede, KE, Martens, L, Elkrim, Y, Debraekeleer, A, Stijlemans, B, Vandekeere, A, Rinaldi, G, De Rycke, R, Planque, M, Broekaert, D, Meinster, E, Clappaert, E, Bardet, P, Murgaski, A, Gysemans, C, Nana, FA, Saeys, Y, Bendall, SC, Laoui, D, Van den Bossche, J, Fendt, SM & Van Ginderachter, JA 2021, 'Macrophages are metabolically heterogeneous within the tumor microenvironment', Cell reports, vol. 37, no. 13, 110171. https://doi.org/10.1016/j.celrep.2021.110171

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 - Funding Information: This work was supported by a PhD fellowship of the Research Foundation ? Flanders (FWO) and a national Belgian fellowship L'Or?al-UNESCO ?For Women in Science? to X.G. J.F.-G. A.V. and G.R. are/were supported by FWO fellowships. J.V.d.B. received a VENI grant from ZonMW (91615052), a Netherlands Heart Foundation Junior Postdoctoral grant (2013T003), a Senior Fellowship (2017T048), and a NWO ENW-KLEIN-1 grant (268). S.-M.F. acknowledges funding from the European Research Council under the ERC Consolidator grant agreement no. 771486?MetaRegulation, FWO Projects, KU Leuven ? FTBO, and Fonds Baillet Latour. J.A.V.G. is supported by grants from Kom op tegen Kanker, Stichting tegen Kanker, and FWO-Vlaanderen. The authors would like to thank Jan Brughmans, Solange Martins, Maryse Schmoetten, Ella Omasta, Marie-Th?r?se Detobel, Nickey Riebeek, Maria Slazak, and Nadia Abou for technical and administrative support. We thank Isabelle Scheyltjens for advice regarding Metascape analysis. Bulk RNA sequencing and analyses were performed by VIB Nucleomics Core (www.nucleomics.be). We thank Benjamin Pavie, Anneke Kremer, and Eef Parthoens from VIB Bioimaging Core-Gent for their support with confocal/electron microscopy analysis and Bart Ghesqui?re from VIB Metabolomics Core. We thank Janick Mathys from VIB for advice regarding statistical analysis. Conceptualization, X.G. J.V.d.B. S.-M.F. and J.A.V.G.; formal analysis, X.G. J.F.-G. F.J.H. K.E.d.G. L.M. A.V. G.R. R.D.R. and M.P.; investigation, X.G. F.J.H. K.E.d.G. Y.E. A.D. B.S. A.V. G.R. R.D.R. D.B. E.M. E.C. P.B. A.M. and C.G.; resources ? provision of patient samples, F.A.N.; writing ? original draft preparation, X.G.; writing ? review & editing: X.G. J.V.d.B. S.-M.F. and J.A.V.G.; visualization: X.G. F.J.H. and L.M.; supervision: Y.S. S.C.B. D.L. J.V.d.B. S.-M.F. and J.A.V.G.; funding acquisition: J.V.d.B. S.-M.F. and J.A.V.G. J.A.V.G. received funding from Precirix, Argenx, and Oncurious for projects unrelated to this manuscript and has functioned as a consultant for MSD and Fund+. S.-M.F. has received funding from Bayer, Merck, and Black Belt Therapeutics for different projects and is on the editorial board of Cell Reports. All other authors declare no competing interests. Funding Information: J.A.V.G. received funding from Precirix, Argenx, and Oncurious for projects unrelated to this manuscript and has functioned as a consultant for MSD and Fund+. S.-M.F. has received funding from Bayer, Merck, and Black Belt Therapeutics for different projects and is on the editorial board of Cell Reports. All other authors declare no competing interests. Funding Information: This work was supported by a PhD fellowship of the Research Foundation – Flanders (FWO) and a national Belgian fellowship L’Oréal-UNESCO “For Women in Science” to X.G. J.F.-G., A.V., and G.R. are/were supported by FWO fellowships. J.V.d.B. received a VENI grant from ZonMW ( 91615052 ), a Netherlands Heart Foundation Junior Postdoctoral grant ( 2013T003 ), a Senior Fellowship ( 2017T048 ), and a NWO ENW-KLEIN-1 grant ( 268 ). S.-M.F. acknowledges funding from the European Research Council under the ERC Consolidator grant agreement no. 771486 –MetaRegulation, FWO Projects, KU Leuven – FTBO, and Fonds Baillet Latour. J.A.V.G. is supported by grants from Kom op tegen Kanker, Stichting tegen Kanker, and FWO-Vlaanderen. The authors would like to thank Jan Brughmans, Solange Martins, Maryse Schmoetten, Ella Omasta, Marie-Thérèse Detobel, Nickey Riebeek, Maria Slazak, and Nadia Abou for technical and administrative support. We thank Isabelle Scheyltjens for advice regarding Metascape analysis. Bulk RNA sequencing and analyses were performed by VIB Nucleomics Core ( www.nucleomics.be ). We thank Benjamin Pavie, Anneke Kremer, and Eef Parthoens from VIB Bioimaging Core-Gent for their support with confocal/electron microscopy analysis and Bart Ghesquière from VIB Metabolomics Core. We thank Janick Mathys from VIB for advice regarding statistical analysis. Publisher Copyright: © 2021 The Authors

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 - TCA cycle break

KW - immunometabolism

KW - immunosuppression

KW - lactate

KW - macrophage metabolism

KW - metabolomics

KW - non-small-cell lung carcinoma

KW - single-cell metabolic profiling

KW - tumor microenvironment

KW - tumor-associated macrophages

UR - http://www.scopus.com/inward/record.url?scp=85121698675&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.celrep.2021.110171

DO - https://doi.org/10.1016/j.celrep.2021.110171

M3 - Article

C2 - 34965415

SN - 2211-1247

VL - 37

JO - Cell reports

JF - Cell reports

IS - 13

M1 - 110171

ER -

Macrophages are metabolically heterogeneous within the tumor microenvironment

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Keywords

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