Therapeutic potential of tyrosine kinase 2 in autoimmunity

Liang, Yan; Zhu, Yan; Xia, Yi; Peng, Hui; Yang, Xiao‐Ke; Liu, Yanyan; Xu, Wang‐Dong; Pan, Hai‐Feng; Ye, Dong-Qing

doi:10.1517/14728222.2014.892925

Cited by 25 publications

(18 citation statements)

References 93 publications

(43 reference statements)

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“…Patient SS13 had both TYK2-UPF1 and COL25A1-NFKB2 fusion events. The TYK2 gene was shown to be essential for the differentiation and function of different immune cells, including natural killer cells, B cells, and T-helper cells (Liang et al, 2014). The gene NFKB2 is a pleiotropic transcription factor that is involved in several pathways including NF-kB signaling, which regulates the transcription of many genes involved in cancer initiation and progression.…”

Section: Fusion Eventsmentioning

confidence: 99%

Identification of Gene Mutations and Fusion Genes in Patients with Sézary Syndrome

Prasad

Rabionet

Espinet

et al. 2016

Journal of Investigative Dermatology

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Sézary syndrome is a leukemic form of cutaneous T-cell lymphoma with an aggressive clinical course. The genetic etiology of the disease is poorly understood, with chromosomal abnormalities and mutations in some genes being involved in the disease. The goal of our study was to understand the genetic basis of the disease by looking for driver gene mutations and fusion genes in 15 erythrodermic patients with circulating Sézary cells, 14 of them fulfilling the diagnostic criteria of Sézary syndrome. We have discovered genes that could be involved in the pathogenesis of Sézary syndrome. Some of the genes that are affected by somatic point mutations include ITPR1, ITPR2, DSC1, RIPK2, IL6, and RAG2, with some of them mutated in more than one patient. We observed several somatic copy number variations shared between patients, including deletions and duplications of large segments of chromosome 17. Genes with potential function in the T-cell receptor signaling pathway and tumorigenesis were disrupted in Sézary syndrome patients, for example, CBLB, RASA2, BCL7C, RAMP3, TBRG4, and DAD1. Furthermore, we discovered several fusion events of interest involving RASA2, NFKB2, BCR, FASN, ZEB1, TYK2, and SGMS1. Our work has implications for the development of potential therapeutic approaches for this aggressive disease.

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Section: Fusion Eventsmentioning

confidence: 99%

Identification of Gene Mutations and Fusion Genes in Patients with Sézary Syndrome

Prasad

Rabionet

Espinet

et al. 2016

Journal of Investigative Dermatology

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“…13,14 The first TYK2 specific inhibitors have been recently developed and are considered as promising therapeutic agents for the treatment of inflammatory and autoimmune diseases. [15][16][17][18][19][20] Very recently, tumor cell-intrinsic TYK2 activity has been linked to the development of T cell acute lymphoblastic leukemia (T-ALL) and cutaneous T cell lymphoma development in humans. 21,22 Therefore, specific inhibition of TYK2 activity might be considered as a new therapeutic opportunity for some hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

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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“…JAK/ STAT signaling components are frequently altered in cancers, and considerable effort is directed toward the development of specific inhibitors for tumor therapy (21)(22)(23)(24). TYK2 inhibitors are considered for the treatment of inflammatory diseases and tumor therapy (25)(26)(27)(28)(29)(30)(31)(32). However, to realize their full potential and to identify harmful side effects, a better understanding of how TYK2 regulates NK cell function and antitumor activity is required.…”

mentioning

confidence: 99%

NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity

Simonović

Witalisz-Siepracka

Meissl

et al. 2019

The Journal of Immunology

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Tyrosine kinase 2 (TYK2) is a widely expressed receptor-associated kinase that is involved in signaling by a variety of cytokines with important immune regulatory activities. Absence of TYK2 in mice results in impaired NK cell maturation and antitumor activity, although underlying mechanisms are largely unknown. Using conditional ablation of TYK2 in NK cells we show that TYK2 is required for IFN-g production by NK cells in response to IL-12 and for an efficient immune defense against Listeria monocytogenes. Deletion of TYK2 in NK cells did not impact NK cell maturation and IFN-g production upon NK cell activating receptor (actR) stimulation. Similarly, NK cell-mediated tumor surveillance was unimpaired upon deletion of TYK2 in NK cells only. In line with the previously reported maturation-associated Ifng promoter demethylation, the less mature phenotype of Tyk2 2/2 NK cells correlated with an increased CpG methylation at the Ifng locus. Treatment with the DNA hypomethylating agent 5-aza-2-deoxycytidine restored the ability of Tyk2 2/2 NK cells to produce IFN-g upon actR but not upon IL-12 stimulation. NK cell maturation was dependent on the presence of TYK2 in dendritic cells and could be rescued in Tyk2-deficient mice by treatment with exogenous IL-15/IL-15Ra complexes. IL-15 treatment also rescued the in vitro cytotoxicity defect and the impaired actR-induced IFN-g production of Tyk2 2/2 NK cells. Collectively, our findings provide the first evidence, to our knowledge, for a key role of TYK2 in the host environment in promoting NK cell maturation and antitumor activity.

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Therapeutic potential of tyrosine kinase 2 in autoimmunity

Cited by 25 publications

References 93 publications

Identification of Gene Mutations and Fusion Genes in Patients with Sézary Syndrome

Identification of Gene Mutations and Fusion Genes in Patients with Sézary Syndrome

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

NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity

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