Macrophages are metabolically heterogeneous within the tumor microenvironment

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

doi:10.1016/j.celrep.2021.110171

Cited by 94 publications

(62 citation statements)

References 101 publications

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“…Despite the widely recognized limitations surrounding in vitro experiments, a prolonged lag in pushing towards in vivo studies has hindered advances in mph immunometabolism (Van den Bossche and Saraber, 2018). Flow-based analysis of metabolic enzyme expression has been demonstrated as a technique to investigate metabolic features of immune cell populations from blood (Ahl et al ., 2020; Hartmann et al ., 2021) or tumors (Geeraerts et al ., 2021; Levine et al, 2021). Here, to the first of our knowledge, we present the use of spectral flow cytometry for high dimensional analysis of tissue mphs, adapting ‘met-flow’ to interrogate mph metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Metabolic flow or mass cytometry targeting nutrient transporters and enzymes has recently been pioneered as a highly promising alternative to analyze immune metabolism at the single-cell level (Ahl et al, 2020; Geeraerts et al, 2021; Hartmann et al, 2021). These methods for metabolic analysis have yet to define the tissue-specific metabolic states, or responses, of mphs.…”

Section: Introductionmentioning

confidence: 99%

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Spectral flow cytometry reveals metabolic heterogeneity in tissue macrophages

Heieis

Patente

Tak

et al. 2022

Preprint

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Tissue-macrophage populations are constituted by a mosaic of phenotypes, yet new methods are needed to link metabolic status to the range of phenotypes in vivo. We therefore designed a high-dimensional panel for spectral flow cytometry to investigate the heterogeneity of tissue macrophage metabolism at steady-state, and their metabolic adaptation in response to infection. Distinct metabolic profiles were observed between tissue macrophages from different peripheral organs, as well as within populations from a specific site. As such, our data show multiple metabolic states in macrophages corresponding to relative stages of maturity in both the peritoneal cavity and small intestine. Immune perturbation with helminth infection further showed that peritoneal macrophages acquire an overall highly metabolically active profile, whereas responding intestinal macrophages displayed minimal changes in their metabolic phenotype. Thus, we demonstrate that high-dimensional, flow-based analysis is an exciting method to interrogate the metabolic heterogeneity and dynamics of tissue-macrophage populations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spectral flow cytometry reveals metabolic heterogeneity in tissue macrophages

Heieis

Patente

Tak

et al. 2022

Preprint

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“…Furthermore, lactate has been shown to have differential metabolic roles within the TAM subpopulations in the TME. For example, lactate diminishes glycolytic activity in M1/MHC-II hi TAMs, but upregulates the TCA cycle, enhances Arg1, NOS2 expressions in MHC-II lo TAMs, resulting in suppression of T cell proliferation ( 51 ). We observed TAM phagocytosis suppression and decreased myeloid M1 signatures with corresponding high glycolytic activity in bone and lymph node metastatic PC patients, respectively, validating our mechanistic findings in advanced PC patients.…”

Section: Discussionmentioning

confidence: 99%

“…To perform in vitro macrophage functionality assay, bone marrow progenitors were extracted from femur of male Cre -/- GEMM mice by flushing twice with cold PBS buffer. Progenitors were cultured for 7 days in M-CSF (30 ng/mL) containing DMEM media supplemented with 10% FBS, 1% non-essential amino acid and 1% penicillin/streptomycin, to enable differentiation into bone marrow derived macrophages (BMDM, ( 51 )), which were utilized for downstream functional studies.…”

Section: Materials and Methods (Table S2 Contains Detail On Chemical ...mentioning

confidence: 99%

Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer

Chaudagar

Hieromnimon

Khurana

et al. 2022

Preprint

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PTEN loss-of-function occurs in approximately 50% of mCRPC patients, and is associated with a poor prognosis, therapeutic outcomes and resistance to immune-checkpoint inhibitors. Recent clinical studies demonstrated that dual PI3K/AKT pathway inhibition and androgen axis blockade led to a modest improvement in progression-free survival of PTEN-deficient mCRPC patients, but the mechanistic basis for this limited efficacy is unknown. To elucidate potential resistance mechanism(s), we performed co-clinical trials in a prostate-specific PTEN/p53-deficient genetically-engineered mouse model, and discovered that the recruitment of PD-1-expressing tumor-associated macrophages (TAM) thwarts the phagocytosis-mediated anti-tumor efficacy of androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki) combination. Strikingly, we observed a TAM-dependent ∼3-fold enhancement in the overall response rate with the addition of PD-1 antibody (aPD-1) to ADT/PI3Ki combination therapy. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation (H3K18lac) within TAM, resulting in their phagocytic activation, which was augmented by concurrent ADT/aPD-1 treatment. Consistent with our murine observations, single cell RNA-sequencing analysis of human metastatic PC samples revealed a direct correlation between high glycolytic activity and phagocytosis suppression. Critically, feedback activation of Wnt/β-catenin signaling observed in non-responder mice following ADT/PI3Ki/aPD-1 combination treatment, restored lactate-mediated H3K18lac and suppressed phagocytosis within macrophages. Altogether, these data suggest that reversal of lactate and PD-1-mediated TAM immunosuppression by PI3Ki and aPD-1, respectively, controls tumor growth in combination with ADT, and warrants further clinical investigation in PTEN/p53-deficient mCRPC patients.One Sentence SummaryInhibition of tumor-cell intrinsic lactate production suppresses PTEN/p53-deficient prostate cancer growth via macrophage activation/phagocytosis

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“… 42 43 Within the hypoxic microenvironment, metabolites like lactate are sensed by several cell types, generally suppressing immune functions. 44 Indeed, hypoxic MHC lo TAMs use extracellular lactate to fuel TCA and respiration, 45 and in particular tumor-released lactate sustains TAMs’ protumor functions through hypoxia-inducible factor 1α. 46 Interestingly, TAMs have the highest uptake of glucose within the TME, and glycolysis is thought to support the maintenance of TAMs’ protumoral features in certain contexts.…”

Section: Macrophages In Cancermentioning

confidence: 99%

Lipid-loaded macrophages as new therapeutic target in cancer

Marelli

Morina

Portale

et al. 2022

J Immunother Cancer

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Macrophages are main players of the innate immune system. They show great heterogeneity and play diverse functions that include support to development, sustenance of tissue homeostasis and defense against infections. Dysfunctional macrophages have been described in multiple pathologies including cancer. Indeed tumor-associated macrophages (TAMs) are abundant in most tumors and sustain cancer growth, promote invasion and mediate immune evasion. Importantly, lipid metabolism influences macrophage activation and lipid accumulation confers pathogenic features on macrophages. Notably, a subset of lipid-loaded macrophages has been recently identified in many tumor types. Lipid-loaded TAMs support tumor growth and progression and exert immune-suppressive activities. In this review, we describe the role of lipid metabolism in macrophage activation in physiology and pathology and we discuss the impact of lipid accumulation in macrophages in the context of cancer.

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Macrophages are metabolically heterogeneous within the tumor microenvironment

Cited by 94 publications

References 101 publications

Spectral flow cytometry reveals metabolic heterogeneity in tissue macrophages

Spectral flow cytometry reveals metabolic heterogeneity in tissue macrophages

Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer

Lipid-loaded macrophages as new therapeutic target in cancer

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