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Activin A and NK cell function

ABSTRACT: Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastasis spread. Signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming grow factor (TGF)- is a recognized suppressor of NK cells that inhibits IL-15 dependent signaling events and induces cellular transdifferentiation, however the role of other SMAD signaling pathways in NK cells is unknown. We used a global, label-free proteomics approach to compare the protein expression profiles of NK cells in the presence of TGF-b or activin-A.

INSTRUMENT(S): impact II

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Natural Killer Cell

SUBMITTER: Laura Dagley

LAB HEAD: Fernando Souza-Fonseca-Guimaraes

PROVIDER: PXD011672 | Pride | 2020-04-06

REPOSITORIES: Pride

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Publications

Therapeutic blockade of activin-A improves NK cell function and antitumor immunity.

Rautela Jai J Dagley Laura F LF de Oliveira Carolina C CC Schuster Iona S IS Hediyeh-Zadeh Soroor S Delconte Rebecca B RB Cursons Joseph J Hennessy Robert R Hutchinson Dana S DS Harrison Craig C Kita Badia B Vivier Eric E Webb Andrew I AI Degli-Esposti Mariapia A MA Davis Melissa J MJ Huntington Nicholas D ND Souza-Fonseca-Guimaraes Fernando F

Science signaling 20190827 596

Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastatic spread. The signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming growth factor-β (TGF-β) is a suppressor of NK cells that inhibits interleukin-15 (IL-15)-dependent signaling events and increases the abundance of receptors that promote tissue residency. Here, we showed that NK cells expr ...[more]

PMID: 31455725

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TGF-β and CIS inhibition overcomes NK cell suppression to restore anti-tumor immunity

Project description:Antibodies targeting “immune checkpoints” have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8 T cells. Interest in targeting analogous pathways in other cytotoxic lymphocytes is growing. Natural killer (NK) cells are key to cancer immunosurveillance by eradicating metastases and driving solid tumor inflammation. NK cell anti-tumor function is dependent on the cytokine interleukin (IL)-15. Ablation of the IL-15 signaling inhibitor CIS (Cish) enhances NK cell anti-tumor immunity by increasing NK cell metabolism and persistence within the tumor microenvironment (TME). The TME has also been shown to impair NK cell fitness via the production of immunosuppressive TGF-b, a suppression which occurs even in the presence of high IL-15 signaling. Here, we identified an unexpected interaction between CIS and the TGF-b signaling pathway in NK cells. Independently, Cish- and Tgfbr2- deficient NK cells are both hyper-responsive to IL-15 and hypo-responsive to TGF-b, with dramatically enhanced anti-tumor immunity. Remarkably, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development, suggesting that combining suppression of these two pathways might represent a novel therapeutic strategy to enhance innate anti-cancer immunity.

2022-04-11 | GSE200134 | GEO

Regulatory NK cells: IL-18-elicited NK cells with immunosuppressive functions

Project description:Cancer-induced tolerance mostly involves myeloid suppressor cells, regulatory T cells and immunosuppressive cytokines, which all subvert adaptive immune responses against tumor cells. Here, we show that a subset of innate effectors, c-kit expressing NK cells (Kit+ NK), can participate in tumor-induced tolerance by compromising the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells can convert Kit- into Kit+ NK cells that overexpress B7-H1/PD-L1 molecules. Upon tumor inoculation, Kit+ NK cells rapidly develop in lymphoid organs in a IL-18R/MyD88 dependent manner and directly kill Kit- NK cells in a B7-H1/PD-1-dependent manner, thereby promoting the progression of NK-controlled cancers. Our data suggest that, in a tumoral context, IL-18 subverts antitumor NK cell functions. Systemic neutralization of IL-18 by IL-18-binding protein may improve the NK-mediated immunosurveillance. Keywords: cell type comparison

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Proteomic analysis of NK cell-derived extracellular vesicles.

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2020-04-03 | PXD014894 | Pride

Real-time quantitative PCR analysis reveals high expression of activin A during NK-DC interactions

Project description:The interaction of natural killer (NK) cells with dendritic cells (DC) results in reciprocal cell activation through the interaction of membrane proteins and the release of soluble factors. Here we report that in NK-DC cocultures, among a set of 84 cytokines investigated, activin A was the second highest induced gene, with CXCL8 being the most upregulated one. Activin A is a member of the TGF-M-NM-2 superfamily and was previously shown to possess both pro- and antiinflammatory activities. In NK-DC cocultures, the induction of activin A required cell contact and was dependent on the presence of proinflammatory cytokines (i.e. IFN-M-NM-3, TNF-M-NM-1 and GM-CSF) as well as on NK cell-mediated DC killing. CD1+ DC were the main activin A producer cells among myeloid blood DC subsets. In NK-DC cocultures, inhibition of acitivn A by follistatin, a natural inhibitory protein, or by a specific blocking antibody, resulted in the upregulation of proinflammatory cytokine release (i.e. IL-6, IL-8, TNF-M-NM-1) by DC and in the increase of DC maturation. In conclusion, our study reports that activin A, produced during NK-DC interactions, represents a relevant negative feedback mechanism that might function to prevent excessive immune activation by DC. Human CD14 positive monocytes were differentiated to DC in vitro in the presence of IL-4 (20 ng/ml) and GM-CSF (50 ng/ml) for 6 days. Immature DC were then cocultured with allogeneic IL-15-activated NK cells (at 1:1 NK:DC ratio) for 0, 2 and 6 hrs. RNA was obtained from three independent coculture experiments. Equal amount of total RNA from each experiment was pooled prior to gene expression analysis. The gene expression of common cytokines was quantified using an RT2 Profiler PCR Array (Qiagen).

2013-11-13 | E-GEOD-52306 | biostudies-arrayexpress

Real-time quantitative PCR analysis reveals high expression of activin A during NK-DC interactions

Project description:The interaction of natural killer (NK) cells with dendritic cells (DC) results in reciprocal cell activation through the interaction of membrane proteins and the release of soluble factors. Here we report that in NK-DC cocultures, among a set of 84 cytokines investigated, activin A was the second highest induced gene, with CXCL8 being the most upregulated one. Activin A is a member of the TGF-β superfamily and was previously shown to possess both pro- and antiinflammatory activities. In NK-DC cocultures, the induction of activin A required cell contact and was dependent on the presence of proinflammatory cytokines (i.e. IFN-γ, TNF-α and GM-CSF) as well as on NK cell-mediated DC killing. CD1+ DC were the main activin A producer cells among myeloid blood DC subsets. In NK-DC cocultures, inhibition of acitivn A by follistatin, a natural inhibitory protein, or by a specific blocking antibody, resulted in the upregulation of proinflammatory cytokine release (i.e. IL-6, IL-8, TNF-α) by DC and in the increase of DC maturation. In conclusion, our study reports that activin A, produced during NK-DC interactions, represents a relevant negative feedback mechanism that might function to prevent excessive immune activation by DC.

2013-11-13 | GSE52306 | GEO

Microarray analysis of resting Nkrp1g+ NK cells versus resting Nkrp1g- NK cells from spleens of female BALB/c mice.

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2017-11-21 | E-MTAB-6223 | biostudies-arrayexpress

CD137 costimulation counteracts TGFβ inhibition of NK cell anti-tumor function and promotes the acquisition of tissue-resident Th9-like properties [2 treatments]

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2023-04-26 | GSE226160 | GEO

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