T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response

Sitkovsky, Michail V.

doi:10.1016/j.it.2008.12.002

Cited by 169 publications

(165 citation statements)

References 57 publications

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“…Increased NF-κB activity was observed in hepatocellular carcinoma cells that developed sorafenib resistance (36), which is of interest because the antiangiogenic effects of sorafenib induce intratumoral hypoxia that causes HIF-1-dependent induction of breast CSCs (19). Immunosuppressive functional interactions of HIF-1 and CREB have been proposed in T cells (47), but may also occur in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…CRT expression was induced by exposure of cardiomyocytes to hypoxia and reoxygenation (51), suggesting that the increased phagocytosis of NTC and DKD subclones after hypoxic exposure may be due to HIF-independent CRT expression, but further studies are required to test this hypothesis. A recent report demonstrated that CD47 blockade also promotes T-cell-mediated elimination of immunogenic tumors (52) and HIF-1 is known to inhibit effector T cells through the production of adenosine (23,47), suggesting that HIF inhibitors may improve the response to CD47 blockade both by inhibiting CD47 expression and by disinhibiting T-cell-mediated antitumor immunity.…”

Section: Discussionmentioning

confidence: 99%

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HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

Zhang

Xiang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

341

256

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Increased expression of CD47 has been reported to enable cancer cells to evade phagocytosis by macrophages and to promote the cancer stem cell phenotype, but the molecular mechanisms regulating CD47 expression have not been determined. Here we report that hypoxia-inducible factor 1 (HIF-1) directly activates transcription of the CD47 gene in hypoxic breast cancer cells. Knockdown of HIF activity or CD47 expression increased the phagocytosis of breast cancer cells by bone marrow-derived macrophages. CD47 expression was increased in mammosphere cultures, which are enriched for cancer stem cells, and CD47 deficiency led to cancer stem cell depletion. Analysis of datasets derived from thousands of patients with breast cancer revealed that CD47 expression was correlated with HIF target gene expression and with patient mortality. Thus, CD47 expression contributes to the lethal breast cancer phenotype that is mediated by HIF-1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

Zhang

Xiang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

341

256

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“…5 T lymphocytes appear to mainly utilize A 2A R, whereby ADO interacting with the receptor transmits immunosuppressive signals, leading to activation of adenylyl cyclase (AC), upregulation of cAMP levels and inhibition of Teff functions. 6,7 In contrast, peripheral regulatory T cells (pTreg) or myeloid-derived suppressor cells (MDSC) are activated by ADO signaling via A 2A R and their immunosuppressive functions are enhanced. 8,9 The role of A 1 R or A 3 R in ADO-mediated immune regulation is not entirely clear, although 5 0 -AMP was reported to be an A 1 R agonist with affinity equal to or better than that of ADO.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)

et al. 2016

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CD39 and CD73 are key enzymes in the adenosine (ADO) pathway. ADO modulates pathophysiological responses of immune cells, including B cells. It has recently emerged that a subpopulation of ADOproducing CD39 C CD73 C B cells has regulatory properties. Here, we define the CD39 high subset of these cells as the major contributor to the regulatory network operated by human B lymphocytes. Peripheral blood B cells were sorted into CD39 neg , CD39 inter and CD39 high subsets. The phenotype, proliferation and IL-10 secretion by these B cells were studied by flow cytometry. 5 0 -AMP and ADO levels were measured by mass spectrometry. Agonists or antagonists of A 1 R, A 2A R and A 3 R were used to study ADO-

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“…Adenosine and T reg cell interaction tumor microenvironment As described earlier, tumor microenvironment has hypoxic condition within it and extracellular adenosine-rich microenvironment, both favoring induction of development T regs [215]. Additionally, increased infiltration of tumors with T regs is well correlated with the poor prognosis of various kinds of tumors (i.e., ovarian cancers, nonsmall cell lung cancer, Hodgkin's lymphoma, etc.)…”

Section: Infiltration Of T Reg Cells In Tumor Microenvironmentmentioning

confidence: 89%

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

Kumar

2012

Purinergic Signalling

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Cancer is a chronic disease and its pathogenesis is well correlated with infection and inflammation. Adenosine is a purine nucleoside, which is produced under metabolic stress like hypoxic conditions. Acute or chronic inflammatory conditions lead to the release of precursor adenine nucleotides (adenosine triphosphate (ATP), adenosien diphosphate (ADP) and adenosine monophosphate (AMP)) from cells, which are extracellularly catabolized into adenosine by extracellular ectonucleotidases, i.e., CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. It is now well-known that adenosine is secreted by cancer as well as immune cells during tumor pathogenesis under metabolic stress or hypoxia. Once adenosine is released into the extracellular environment, it exerts various immunomodulatory effects via adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) expressed on various immune cells (i.e., macrophages, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, dendritic cells (DCs), T cells, regulatory T cell (T regs ), etc.), which play very important roles in the pathogenesis of cancer. This review is intended to summarize the role of inflammation and adenosine in the immunopathogenesis of tumor along with regulation of tumor-specific immune response and its modulation as an adjunct approach to tumor immunotherapy.

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T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response

Cited by 169 publications

References 57 publications

HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

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T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response

Cited by 169 publications

References 57 publications

HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

Phenotypic and functional characteristics of CD39highhuman regulatory B cells (Breg)

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

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Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)