Loss of STAT3 in murine NK cells enhances NK cell–dependent tumor surveillance

Gotthardt, Dagmar; Putz, Eva Maria; Straka, Elisabeth; Kudweis, Petra; Biaggio, Mario; Poli, Valeria; Strobl, Birgit; Müller, Mathias; Sexl, Veronika

doi:10.1182/blood-2014-03-564450

Cited by 98 publications

(101 citation statements)

References 44 publications

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“…Expression of NKG2D in splenic NK cells from na€ ıve mice is regulated in a STAT3-dependent, STAT1-and IFNAR1-independent manner, 40,50 suggesting a link between TYK2 and STAT3 functions. However, TYK2 deficiency did not recapitulate the increased expression of DNAM-1, GZMB and PRF1 reported in STAT3-deficient NK cells, 51 arguing against a general impairment of STAT3 activity in the absence of TYK2. Interestingly, expression of TYK2 K923E restores NKG2D expression but results in increased expression of DNAM-1.…”

Section: Discussionmentioning

confidence: 87%

In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

et al. 2015

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Abbreviations: CCL3, chemokine (C-C motif) ligand 3; CFSE, carboxyfluorescein diacetate succinimidyl ester; GzmB, granzyme B; IFN, interferon; IFNAR, interferon a and b receptor; IL, interleukin; IL-12Rb1, interleukin-12 receptor subunit b-1; iNK, immature natural killer; JAK, xJanus kinase; MACS, magnetic-activated cell sorting; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; miR, microRNA; mNK, mature natural killer; NK, natural killer; NKP, natural killer precursor; Prf1, perforin; SEM, standard error of the mean; STAT, signal transducer and activator of transcription; T-ALL, T cell acute lymphoblastic leukemia; TYK2, tyrosine kinase 2; TYK2 K923E , kinase-inactive tyrosine kinase 2; WT, wild-typeTyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2 ¡/¡ ) mice is severely reduced, although the underlying mechanisms are largely unknown. Using Tyk2 ¡/¡ mice and mice expressing a kinase-inactive version of TYK2 (Tyk2 K923E ), we show that NK cell function is partly independent of the enzymatic activity of TYK2. Tyk2 ¡/¡ and Tyk2 K923E NK cells develop normally in the bone marrow, but the maturation of splenic Tyk2 ¡/¡ NK cells (and to a lesser extent of Tyk2 K923E NK cells) is impaired. In contrast, the production of interferon g (IFNg) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity of Tyk2 K923E NK cells against a range of target cells in vitro is higher than that of Tyk2 ¡/¡ NK cells. Consistently, Tyk2 K923E mice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2's kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functions in vivo suggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy.

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Section: Discussionmentioning

confidence: 87%

In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

et al. 2015

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“…The Janus kinase/signal transducer and activator of transcription (STAT) signaling pathway implicated in NK cell development and function [25,26]. Therefore, NK-92 cells were analyzed for Serine phosphorylation (pSer) of STAT1 and STAT3 with STAT1 or STAT3 antibodies by western blotting.…”

Section: Hbv Antigens Suppressed Multi-signaling Pathways Associated mentioning

confidence: 99%

Hepatitis B virus antigens impair NK cell function

Yang

Han

Zhang

et al. 2016

International Immunopharmacology

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“…While cytokines such as IL-12, IL-15, IL-21, and type I IFNs induce STAT3 tyrosine phosphorylation in NK-cells, the most potent activation is achieved by treatment with the immunosuppressive and anti-inflammatory cytokine IL-10 (71). Many tumors harbor constitutively active STAT3 that triggers the release of immunosuppressive cytokines such as IL-10 or TGF-β.…”

Section: The Ugly: Stat3: Avoiding Autoimmunity or The Target For Nk-mentioning

confidence: 99%

STATs in NK-Cells: The Good, the Bad, and the Ugly

Gotthardt

Sexl

2017

Front. Immunol.

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Natural killer (NK)-cells are major players in the fight against viral infections and transformed cells, but there is increasing evidence attributing a disease-promoting role to NK-cells. Cytokines present in the tumor microenvironment shape NK-cell maturation, function, and effector responses. Many cytokines signal via the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway that is also frequently altered and constitutively active in a broad range of tumor cells. As a consequence, there are currently major efforts to develop therapeutic strategies to target this pathway. Therefore, it is of utmost importance to understand the role and contributions of JAK–STAT molecules in NK-cell biology—only this knowledge will allow us to predict effects of JAK–STAT inhibition for NK-cell functions and to successfully apply precision medicine. We will review the current knowledge on the role of JAK–STAT signaling for NK-cell functions and discuss conditions involved in the switch from NK-cell tumor surveillance to disease promotion.

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Loss of STAT3 in murine NK cells enhances NK cell–dependent tumor surveillance

Abstract: Key Points• Loss of STAT3 in NK cells enhances the expression of granzyme B, perforin, and DNAM-1, resulting in enhanced tumor surveillance.• STAT3 binds the IFN-g promoter and interferes with cytokine-induced IFN-g production in NK cells.

Cited by 98 publications

References 44 publications

In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

Hepatitis B virus antigens impair NK cell function

STATs in NK-Cells: The Good, the Bad, and the Ugly

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