Macrophage Expression of Hypoxia-Inducible Factor-1α Suppresses T-Cell Function and Promotes Tumor Progression

Doedens, Andrew L.; Stockmann, Christian; Rubinstein, Mark P.; Liao, Daiqing; Zhang, Na; DeNardo, David G.; Coussens, Lisa M.; Karin, Michael; Goldrath, Ananda W.; Johnson, Randall S.

doi:10.1158/0008-5472.can-10-1439

Cited by 558 publications

(494 citation statements)

References 49 publications

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“…On the same note, Doedens and colleagues reported that macrophage expression of HIF1a suppresses T-cell function and promotes tumor growth (40). On the basis of the results observed in the present study showing the important role of PI3K signaling axis in controlling both HIF1a and HIF2a accumulation in macrophages, we hypothesize that PI3K signaling should promote tumor growth by increasing secretion of proangiogenic factors in TAMs.…”

Section: Pi3kg Signaling In Macrophages Promotes Tumor Growth and Metsupporting

confidence: 84%

A Macrophage-Dominant PI3K Isoform Controls Hypoxia-Induced HIF1α and HIF2α Stability and Tumor Growth, Angiogenesis, and Metastasis

Joshi

Singh

Zulcic

et al. 2014

Molecular Cancer Research

116

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Tumor growth, progression, and response to the hypoxic tumor microenvironment involve the action of hypoxia-inducible transcription factors, HIF1 and HIF2. HIF is a heterodimeric transcription factor containing an inducible HIFa subunit and a constitutively expressed HIFb subunit. The signaling pathways operational in macrophages regulating hypoxia-induced HIFa stabilization remain the subject of intense investigation. Here, it was discovered that the PTEN/PI3K/AKT signaling axis controls hypoxia-induced HIF1a (HIF1A) and HIF2a (EPAS1) stability in macrophages. Using genetic mouse models and pan-PI3K as well as isoform-specific inhibitors, inhibition of the PI3K/AKT pathway blocked the accumulation of HIFa protein and its primary transcriptional target VEGF in response to hypoxia. Moreover, blocking the PI3K/AKT signaling axis promoted the hypoxic degradation of HIFa via the 26S proteasome. Mechanistically, a macrophage-dominant PI3K isoform (p110g) directed tumor growth, angiogenesis, metastasis, and the HIFa/VEGF axis. Moreover, a pan-PI3K inhibitor (SF1126) blocked tumor-induced angiogenesis and inhibited VEGF and other proangiogenic factors secreted by macrophages. These data define a novel molecular mechanism by which PTEN/PI3K/AKT regulates the proteasome-dependent stability of HIFa under hypoxic conditions, a signaling pathway in macrophages that controls tumor-induced angiogenesis and metastasis.

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Section: Pi3kg Signaling In Macrophages Promotes Tumor Growth and Metsupporting

confidence: 84%

A Macrophage-Dominant PI3K Isoform Controls Hypoxia-Induced HIF1α and HIF2α Stability and Tumor Growth, Angiogenesis, and Metastasis

Joshi

Singh

Zulcic

et al. 2014

Molecular Cancer Research

116

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“…HIF-2α was shown to regulate TAM infiltration in murine models of colon and hepatocellular carcinoma [140]. In a model of breast cancer, HIF-1α-deficient TAMs displayed defective capacity to suppress T cell functions [141]. These results endorse the great potential of HIF inhibition in cancer therapy.…”

Section: Molecular Determinants Of Tamcs Functionsmentioning

confidence: 81%

Origin and Functions of Tumor-Associated Myeloid Cells (TAMCs)

Sica

Porta

Morlacchi

et al. 2011

Cancer Microenvironment

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The construction of an inflammatory microenvironment provides the fuel for cancer development and progression. Hence, solid tumors promote the expansion and the recruitment of leukocyte populations, among which tumor-associated myeloid cells (TAMCs) represent a paradigm for cancer-promoting inflammation. TAMCs group heterogeneous phagocytic populations stemming from a common myeloid progenitor (CMP), that orchestrate various aspects of cancer, including: diversion and skewing of adaptive responses; immunosuppression; cell growth; angiogenesis; matrix deposition and remodelling; construction of a metastatic niche and actual metastasis. Several evidence indicate that TAMCs show plasticity and/or functional heterogeneity, suggesting that tumour-derived factors promote their functional "reprogramming" towards protumoral activities. While recent studies have attempted to address the role of microenvironment signals, the interplay between cancer cells, innate and adaptive immunity is now emerging as a crucial step of the TAMCs reprogramming. Here we discuss the evidence for the differentiation of TAMCs during the course of tumor progression and the molecular mechanisms that regulate such event.

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“…As a defining hallmark of the myeloid cell lineage, plasticity allows macrophages to adjust their effector functions to their surrounding environment (49). In response to hypoxic conditions, macrophages modulate their metabolism (50,51), effector functions in inflammatory responses (52), and ability to handle tumor progression or promote T cell stimulation (53). Because PHD3 regulates HIF protein stability (54) and is itself an HIF target gene (25), it can be hypothesized that the differential EGLN3 gene expression in M1(GM-CSF) and M2(M-CSF) macrophages may underlie a distinct response of both macrophage subtypes to hypoxia.…”

Section: Discussionmentioning

confidence: 99%

The Prolyl Hydroxylase PHD3 Identifies Proinflammatory Macrophages and Its Expression Is Regulated by Activin A

Escribese

Sierra‐Filardi

Nieto

et al. 2012

The Journal of Immunology

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Modulation of macrophage polarization underlies the onset and resolution of inflammatory processes, with polarization-specific molecules being actively sought as potential diagnostic and therapeutic tools. Based on their cytokine profile upon exposure to pathogenic stimuli, human monocyte-derived macrophages generated in the presence of GM-CSF or M-CSF are considered as proinflammatory (M1) or anti-inflammatory (M2) macrophages, respectively. We report in this study that the prolyl hydroxylase PHD3-encoding EGLN3 gene is specifically expressed by in vitro-generated proinflammatory M1(GM-CSF) human macrophages at the mRNA and protein level. Immunohistochemical analysis revealed the expression of PHD3 in CD163+ lung macrophages under basal homeostatic conditions, whereas PHD3+ macrophages were abundantly found in tissues undergoing inflammatory responses (e.g., Crohn’s disease and ulcerative colitis) and in tumors. In the case of melanoma, PHD3 expression marked a subset of tumor-associated macrophages that exhibit a weak (e.g., CD163) or absent (e.g., FOLR2) expression of typical M2-polarization markers. EGLN3 gene expression in proinflammatory M1(GM-CSF) macrophages was found to be activin A dependent and could be prevented in the presence of an anti-activin A-blocking Ab or inhibitors of activin receptor-like kinase receptors. Moreover, EGLN3 gene expression was upregulated in response to hypoxia only in M2(M-CSF) macrophages, and the hypoxia-mediated upregulation of EGLN3 expression was significantly impaired by activin A neutralization. These results indicate that EGLN3 gene expression in macrophages is dependent on activin A both under basal and hypoxic conditions and that the expression of the EGLN3-encoded PHD3 prolyl hydroxylase identifies proinflammatory macrophages in vivo and in vitro.

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Macrophage Expression of Hypoxia-Inducible Factor-1α Suppresses T-Cell Function and Promotes Tumor Progression

Cited by 558 publications

References 49 publications

A Macrophage-Dominant PI3K Isoform Controls Hypoxia-Induced HIF1α and HIF2α Stability and Tumor Growth, Angiogenesis, and Metastasis

A Macrophage-Dominant PI3K Isoform Controls Hypoxia-Induced HIF1α and HIF2α Stability and Tumor Growth, Angiogenesis, and Metastasis

Origin and Functions of Tumor-Associated Myeloid Cells (TAMCs)

The Prolyl Hydroxylase PHD3 Identifies Proinflammatory Macrophages and Its Expression Is Regulated by Activin A

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