Dataset Information

Metabolism in tumor-associated macrophages.

ABSTRACT: Macrophages functionally adapt to a diverse set of signals, a process that is critical for their role in maintaining or restoring tissue homeostasis. This process extends to cancer, where macrophages respond to a series of inflammatory and metabolic cues that direct a maladaptive healing response. Tumor-associated macrophages (TAMs) have altered glucose, amino acid, and lipid metabolic profiles, and interfering with this metabolic shift can blunt the ability of macrophages to promote tumor growth, metastasis, and the creation of an immunosuppressive microenvironment. Here we will review changes in metabolites and metabolic pathways in TAMs and link these with the phenotypic and functional properties of the cells. We will also discuss current strategies targeting TAM metabolism as a therapeutic intervention in cancer.

SUBMITTER: Li J

PROVIDER: S-EPMC9094395 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Metabolism in tumor-associated macrophages.

Li Jie J DeNicola Gina M GM Ruffell Brian B

International review of cell and molecular biology 20220221

Macrophages functionally adapt to a diverse set of signals, a process that is critical for their role in maintaining or restoring tissue homeostasis. This process extends to cancer, where macrophages respond to a series of inflammatory and metabolic cues that direct a maladaptive healing response. Tumor-associated macrophages (TAMs) have altered glucose, amino acid, and lipid metabolic profiles, and interfering with this metabolic shift can blunt the ability of macrophages to promote tumor growt ...[more]

PMID: 35461660

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Project description:Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE2, which correlated with the upregulation of numerous NFkB-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu.

Project description:Elevated infiltration of immunosuppressive alternatively polarized (M2) macrophages is associated with poor prognosis in patients with cancer. The tumor microenvironment remarkably orchestrates molecular mechanisms that program these macrophages. Here we identify a novel role for oncogenic Hedgehog (Hh) signaling in programming signature metabolic circuitries that regulate alternative polarization of tumor-associated macrophages. Two immunocompetent orthotopic mouse models of mammary tumors were used to test the effect of inhibiting Hh signaling on tumor-associated macrophages. Treatment with the pharmacologic Hh inhibitor vismodegib induced a significant shift in the profile of tumor-infiltrating macrophages. Mass spectrometry-based metabolomic analysis showed Hh inhibition induced significant alterations in metabolic processes, including metabolic sensing, mitochondrial adaptations, and lipid metabolism. In particular, inhibition of Hh in M2 macrophages reduced flux through the UDP-GlcNAc biosynthesis pathway. Consequently, O-GlcNAc-modification of STAT6 decreased, mitigating the immune-suppressive program of M2 macrophages, and the metabolically demanding M2 macrophages shifted their metabolism and bioenergetics from fatty acid oxidation to glycolysis. M2 macrophages enriched from vismodegib-treated mammary tumors showed characteristically decreased O-GlcNAcylation and altered mitochondrial dynamics. These Hh-inhibited macrophages are reminiscent of inflammatory (M1) macrophages, phenotypically characterized by fragmented mitochondria. This is the first report highlighting the relevance of Hh signaling in controlling a complex metabolic network in immune cells. These data describe a novel immunometabolic function of Hh signaling that can be clinically exploited. SIGNIFICANCE: These findings illustrate that Hh activity regulates a metabolic and bioenergetic regulatory program in tumor-associated macrophages that promotes their immune-suppressive polarization.

Dataset Information

Metabolism in tumor-associated macrophages.

Publications

Metabolism in tumor-associated macrophages.

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