Conversion of Peripheral Blood NK Cells to a Decidual NK-like Phenotype by a Cocktail of Defined Factors

Cerdeira, Ana Sofia; Rajakumar, Augustine; Royle, Caroline; Lo, Agnes S.; Husain, Zaheed; Thadhani, Ravi; Sukhatme, Vikas P.; Karumanchi, S. Ananth; Kopcow, Hernan D.

doi:10.4049/jimmunol.1202582

Cited by 163 publications

(180 citation statements)

References 55 publications

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“…Our data support the idea: These cytokines signal via STAT5 and may help to revert tumor-infi ltrating but exhausted NK cells into killers that produce perforin and IFN γ . Decidual NK cells have previously been shown to possess two types of activity: They normally produce signifi cant amounts of VEGFA, but stimulation with IL15 switches them to cytotoxic cells ( 36 ). We fi nd that cytokines present in the tumor microenvironment, such as IL10, IL12, IL18, IL21, and IFN β , decrease the activity of STAT5 (refl ected by reduced phosphorylation of STAT5 Y694 ) while enhancing expression of VEGFA.…”

Section: Research Articlementioning

confidence: 74%

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

et al. 2016

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Natural killer (NK) cells are tightly regulated by the JAK-STAT signaling pathway and cannot survive in the absence of STAT5. We now report that STAT5-defi cient NK cells can be rescued by overexpression of BCL2. Our experiments defi ne STAT5 as a master regulator of NK-cell proliferation and lytic functions. Although NK cells are generally responsible for killing tumor cells, the rescued STAT5-defi cient NK cells promote tumor formation by producing enhanced levels of the angiogenic factor VEGFA. The importance of VEGFA produced by NK cells was verifi ed by experiments with a conditional knockout of VEGFA in NK cells. We show that STAT5 normally represses the transcription of VEGFA in NK cells, in both mice and humans. These fi ndings reveal that STAT5-directed therapies may have negative effects: In addition to impairing NK-cell-mediated tumor surveillance, they may even promote tumor growth by enhancing angiogenesis. SIGNIFICANCE:The importance of the immune system in effective cancer treatment is widely recognized. We show that the new signal interceptors targeting the JAK-STAT5 pathway may have dangerous side effects that must be taken into account in clinical trials: inhibiting JAK-STAT5 has the potential to promote tumor growth by enhancing NK-cell-mediated angiogenesis. Cancer Discov; 6(4); ©2016 AACR . Ni and Cerwenka, p. 347. See related commentary by INTRODUCTIONNatural killer (NK) cells are innate lymphocytes that develop from a common lymphoid progenitor in the bone marrow ( 1 ). They represent the fi rst line of defense against infected, stressed, and malignant cells. Recent evidence has assigned distinct features and functions to tissue-specifi c NK cells ( 2 ). NK cells have organ-specifi c properties, such as distinct profi les of receptor expression or cytokine production ( 3 ). Uterine NK cells secrete high levels of VEGFA and are involved in placental vascularization. The physiologic functions of other organ-specifi c NK-cell subsets are less well understood ( 4 ). STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor PromotionDagmarAll aspects of NK-cell development are regulated by cytokines, their downstream signaling pathways, and transcriptional regulators. These include key cytokines such as IL2, IL12, IL15, IL18, and IL21 ( 5 ), most of which signal via the common γ chain ( 5 ) and activate the JAK-STAT pathway ( 6 ). JAK kinases (JAK1-3 and TYK2) bind to cytokine receptors and are activated by ligand/receptor binding. The activated kinase phosphorylates STAT transcription factors refs. 6,7 ).Consistent with its function as the major STAT protein downstream of IL7, IL2, and IL15, STAT5 is absolutely essential for conventional NK-cell development and survival; Stat5 Δ / Δ Ncr1-iCre Tg mice lack NK cells ( 8 ). It is also important for lymphoid cell development ( 9 ): STAT5 is constitutively active in a plethora of lymphoid malignancies ( 10 ). Recent studies have described somatic Stat5b mutations as active drivers of lymphoid mali...

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Section: Research Articlementioning

confidence: 74%

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

et al. 2016

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“…It should be noted, however, that others have reported less production of VEGFA by uNK cells (Lash et al 2006, Wallace et al 2014. Like angiogenic processes in other tissues, the expression of VEGFA in uNK cells is induced by hypoxia (Cerdeira et al 2013). Implantation site VEGFA is also contributed to by trophoblasts, uterine stromal cells, and endothelial cells; thus, the specific contributions of uNK cell-derived VEGFA to implantation sites are estimated indirectly and imprecisely from rodent NK cell depletion and reconstitution experiments.…”

Section: Role Of Nk Cells In Normal Decidual Neoangiogenesismentioning

confidence: 99%

Uterine natural killer cells: supervisors of vasculature construction in early decidua basalis

et al. 2015

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Mammalian pregnancy involves tremendous de novo maternal vascular construction to adequately support conceptus development. In early mouse decidua basalis (DB), maternal uterine natural killer (uNK) cells oversee this process directing various aspects during the formation of supportive vascular networks. The uNK cells recruited to early implantation site DB secrete numerous factors that act in the construction of early decidual vessels (neoangiogenesis) as well as in the alteration of the structural components of newly developing and existing vessels (pruning and remodeling). Although decidual and placental development sufficient to support live births occur in the absence of normally functioning uNK cells, development and structure of implantation site are optimized through the presence of normally activated uNK cells. Human NK cells are also recruited to early decidua. Gestational complications including recurrent spontaneous abortion, fetal growth restriction, preeclampsia, and preterm labor are linked with the absence of human NK cell activation via paternally inherited conceptus transplantation antigens. This review summarizes the roles that mouse uNK cells normally play in decidual neoangiogenesis and spiral artery remodeling in mouse pregnancy and briefly discusses changes in early developmental angiogenesis due to placental growth factor deficiency.Reproduction (2015) 149 R91-R102

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“…NK-клетки с ангиогенными свойствами могут индуцироваться из периферических NK-клеток при комбинации гипоксии, TGF-β и де-метилирующих агентов [10]. Опосредованный NK-ангиогенез регулируется МСК в перифери-ческих тканях и способствует индукции репара-тивных процессов после воспаления [45].…”

Section: роль мск в ремоделировании костной тканиunclassified

Role of Mesenchymal Multipotent Stromal Cells in Remodeling of Bone Defects

Киселевский¹,

Anisimova²,

Должикова³

et al. 2018

Med. immunol.

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Conversion of Peripheral Blood NK Cells to a Decidual NK-like Phenotype by a Cocktail of Defined Factors

Cited by 163 publications

References 55 publications

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

Uterine natural killer cells: supervisors of vasculature construction in early decidua basalis

Role of Mesenchymal Multipotent Stromal Cells in Remodeling of Bone Defects

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