Conditional IFNAR1 ablation reveals distinct requirements of Type I IFN signaling for NK cell maturation and tumor surveillance

Mizutani, Tatsumi; Neugebauer, Nina; Putz, Eva Maria; Moritz, Nadine; Simma, Olivia; Zebedin-Brandl, Eva; Gotthardt, Dagmar; Warsch, Wolfgang; Eckelhart, Eva; Kantner, Hans-Peter; Kalinke, Ulrich; Lienenklaus, Stefan; Strobl, Birgit; Müller, Mathias; Sexl, Veronika; Stoiber, Dagmar

doi:10.4161/onci.21284

Cited by 59 publications

(61 citation statements)

References 48 publications

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“…In fact, we found reduced perforin expression in the intratumoral NK cells as compared to splenic NK cells (Fig. 3C), and the intratumoral NK cells showed reduced cytolytic activity as measured by flow cytometry based degranulation assay 19 (Fig. 3D).…”

Section: Cd11bmentioning

confidence: 85%

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

et al. 2016

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Natural killer (NK) cells are known to have effector and cytolytic properties to kill virus infected or tumor cells spontaneously. Due to these properties, NK cells have been used as an adoptive cellular therapy to control tumor growth in various clinical trials but have shown limited clinical benefits. This indicates that our knowledge about phenotypic and functional differences in NK cells within the tumor microenvironment and secondary lymphoid tissues is incomplete. In this work, we report that B16F10 cellinduced melanoma recruits the CD11b C CD27C subset of NK cells at a very early stage during tumor progression. These intratumoral NK cells showed increased expression of CD69, reduced inhibitory receptor KLRG1, and decreased proliferative ability. As compared to splenic NK cells, intratumoral NK cells showed decreased expression of activating receptors NKG2D, Ly49D and Ly49H; increased inhibitory receptors, NKG2A and Ly49A; decreased cytokines IFNg and GM-CSF; decreased cytokine receptors IL-21R, IL-6Ra, and CD122 expression. Depletion of NK cells led to decrease peripheral as well as intratumoral effector CD4 C T-bet C cells (Th1), and increased tumor growth. Furthermore, purified NK cells showed increased differentiation of Th1 cells in an IFNg-dependent manner. Anti-NKG2D in the culture promoted differentiation of effector Th1 cells. Collectively, these observations suggest that intratumoral NK cells possess several inhibitory functions that can be partly reversed by signaling through the NKG2D receptor or by cytokine stimulation, which then leads to increased differentiation of effector Th1 cells.

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Section: Cd11bmentioning

confidence: 85%

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

et al. 2016

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“…35,36 We found lower expression of the NK cell activating receptor NKGD2 in Tyk2 ¡/¡ NK cells. 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.…”

Section: Discussionmentioning

confidence: 99%

“…It seems likely that the role of TYK2 is linked to its role in IFNa/b signaling, as NK cells from both Ifnar1 ¡/¡ and Stat1 ¡/¡ mice have impaired killing activity. [40][41][42]44 Effects on the expression of the lytic proteins GzmB and Prf1 and on degranulation could be excluded as the underlying mechanisms for IFNAR1 40 and TYK2. Furthermore, we show that TYK2 is not required for conjugate formation of NK cells with their target cells.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro NK cell cytotoxicity assays were performed as previously described 40 using YAC-1, RMA-S and RMA-Rae1 as target cells. In vivo cytotoxicity assays were performed as follows: splenocytes from b2m ¡/¡ and WT mice were isolated and stained with carboxyfluorescein diacetate succinimidyl ester (CFSE) according to the manufacturer's instructions (Molecular Probes, CellTrace TM CFSE Cell Proliferation Kit) at 5 mM and 0.5 mM, respectively.…”

Section: Nk Cell Cytotoxicity Assaysmentioning

confidence: 99%

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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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“…Homeostasis of the NK-cell compartment appears to be particularly dependent upon endogenous type-I IFN signaling, as reports have shown that Ifnar1 À/À mice possess a relatively immature pool of these cells (28). Similarly, the dysfunction of the NK-cell compartment in Ifnar1 À/À null mice has been implicated in the establishment of some tumors (16), and more recent data have proven the importance of these cells in preventing the outgrowth of experimental melanoma metastases (29).…”

Section: Type-i Ifns Promote Nk-cell-mediated Elimination Of Breast Tmentioning

confidence: 99%

Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

Rautela

Baschuk

Slaney

et al. 2015

Cancer Immunology Research

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Metastatic progression is the major cause of breast cancerrelated mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1 À/À mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1 À/À mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host hematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating natural killer (NK)-cell population. We find that in vivo-stimulated NK cells derived from wild-type, but not Ifnar1 À/À , mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an antimetastatic strategy.

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Conditional IFNAR1 ablation reveals distinct requirements of Type I IFN signaling for NK cell maturation and tumor surveillance

Cited by 59 publications

References 48 publications

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

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

Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer

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