Metabolism drives macrophage heterogeneity in the tumor microenvironment

Li, Shasha; Yu, Jiali; Huber, Amanda K.; Kryczek, Ilona; Wang, Zhuwen; Jiang, Long; Li, Xiong; Du, Wei; Li, Gaopeng; Wei, Shuang; Vatan, Linda; Szeliga, Wojciech; Chinnaiyan, Arul M.; Green, Michael D.; Cieślik, Marcin; Zou, Weiping

doi:10.1016/j.celrep.2022.110609

Cited by 70 publications

(63 citation statements)

References 67 publications

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“…M2/Th2 associated arginase ( ARG1 ) catalyzes the conversion of cytosolic arginine into ornithine, which can then enter the mitochondria via SLC25A15/SLC25A2-mediated transport 73 to serve as a substrate for proline synthesis. Arginine-ornithine exchange in lower organisms occurs in a 1-to-1 ratio 74 , and the mammalian exchanger SLC15A15 has been shown to mark a subset of myeloid-derived TAMs that are 8-fold more prevalent in tumors than healthy tissues 75 . Overall, our results suggest that mechano-metabolic programming induced by the physical properties of a tissue may instruct and support infiltrating myeloid cell programming to match a presumed stage of wound healing, which is speciously subverted in tumor progression.…”

Section: Discussionmentioning

confidence: 99%

“…To address this, strategies have been developed to ablate TAMs with varying clinical successes, possibly due to the high heterogeneity and plasticity of TAM 57,58 . Indeed, although distinct TAM populations have previously been characterized with flow cytometry based on expression levels of CD11b/CD11c 68,69 , scRNAseq efforts reveal that TAMs possess much greater phenotypic diversity 23,[59][60][61] . Thus, while subsets of TAMs exist that can compromise anti-cancer immunotherapy by releasing CTL-suppressive cytokines, engaging in metabolism that competes for CTL demands, and stimulating fibrosis to impede CTL tumorinfiltration 7,9,62 , not all TAMs exert repression on the adaptive immune system or promote tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, while subsets of TAMs exist that can compromise anti-cancer immunotherapy by releasing CTL-suppressive cytokines, engaging in metabolism that competes for CTL demands, and stimulating fibrosis to impede CTL tumor-infiltration 7,9,62 , not all TAMs exert repression on the adaptive immune system or promote tumor growth. Recent studies have shown that macrophage heterogeneity and function in the TME may be associated with specific metabolic programs 23 . Indeed, we identify the stiff, fibrotic stroma of the tumor as a key regulator of the pro-tumor phenotype through TGFβ signaling and expand this characterization to include its collagen-ECM synthetic ornithine secretory arginine uptake behavior.…”

Section: Discussionmentioning

confidence: 99%

“…However, because T cells import arginine through multifunctional transporters which competitively import a number of structurally similar molecules (e.g., lysine, ornithine, and arginine), the abundance of these competing molecules can dictate whether arginine supplementation improves T cell survival 14 . Tumor infiltrating myeloid cells also acquire an amino acid metabolism signature marked by SLC25A15 23 , the mitochondrial ornithine translocase, which acts downstream of ARG1 for a yet to be determined purpose in this context. Since tumor infiltrating myeloid cells may outcompete T cells for environmental arginine requisite for anti-tumor immunity, it remains to be determined what purpose this metabolic program serves and why it associates with fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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Myeloid mechano-metabolic programming restricts anti-tumor immunity

Tharp

Kersten

Maller

et al. 2022

Preprint

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Tumor progression ensues when the immune system fails to mount a productive anti-tumor response. Inappropriate programming of myeloid cells associates with tissue fibrosis and is accompanied by impaired T cell anti-tumor responses. Here, we demonstrate that myeloid cells respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a wound-healing associated collagen biosynthesis program. A collateral effect of this programming is an untenable metabolic milieu for productive CD8 T cell anti-tumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline, and excrete ornithine that compromises CD8 T cell function. Thus, a stiff and fibrotic TME may impede anti-tumor immunity not only by direct physical exclusion of CD8 T cells, but also via secondary effects of the myeloid mechano-metabolic programming described here that creates an inhospitable metabolic milieu for CD8 T cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Myeloid mechano-metabolic programming restricts anti-tumor immunity

Tharp

Kersten

Maller

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…On the other hand, cancer cells might regulate KC activities directly since liver macrophage activity and function are affected by cancer cells ( 111 ). Cancer cells also change macrophage cytokines-releasing ( 112 ) and metabolism ( 113 ) which further promote HCC progression. Cancer cell-KCs crosstalk exacerbates HCC by initiating a vicious circle which reinforces each other.…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

Heterogeneity and Function of Kupffer Cells in Liver Injury

Chang

2022

Front. Immunol.

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Kupffer cells (KCs) are key regulators of liver immunity composing the principal part of hepatic macrophages even body tissue macrophages. They reside in liver sinusoids towards portal vein. The micro-environment shapes KCs unique immunosuppressive features and functions. KCs express specific surface markers that distinguish from other liver macrophages. By engulfing gut-derived foreign products and apoptotic cells without triggering excessive inflammation, KCs maintain homeostasis of liver and body. Heterogeneity of KCs has been identified in different studies. In terms of the origin, adult KCs are derived from progenitors of both embryo and adult bone marrow. Embryo-derived KCs compose the majority of KCs in healthy and maintain by self-renewal. Bone marrow monocytes replenish massively when embryo-derived KC proliferation are impaired. The phenotype of KCs is also beyond the traditional dogma of M1-M2. Functionally, KCs play central roles in pathogenesis of acute and chronic liver injury. They contribute to each pathological stage of liver disease. By initiating inflammation, regulating fibrosis, cirrhosis and tumor cell proliferation, KCs contribute to the resolution of liver injury and restoration of tissue architecture. The underlying mechanism varied by damage factors and pathology. Understanding the characteristics and functions of KCs may provide opportunities for the therapy of liver injury. Herein, we attempt to afford insights on heterogeneity and functions of KCs in liver injury using the existing findings.

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From monocyte‐derived macrophages to resident macrophages—how metabolism leads their way in cancer

Ammarah,

Pereira‐Nunes,

Delfini

et al. 2024

Molecular Oncology

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Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor‐associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche‐derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype‐specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types.

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Metabolism drives macrophage heterogeneity in the tumor microenvironment

Cited by 70 publications

References 67 publications

Myeloid mechano-metabolic programming restricts anti-tumor immunity

Myeloid mechano-metabolic programming restricts anti-tumor immunity

Heterogeneity and Function of Kupffer Cells in Liver Injury

From monocyte‐derived macrophages to resident macrophages—how metabolism leads their way in cancer

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