Establishing the role of tyrosine kinase 2 in cancer

Übel, Caroline; Mousset, Stéphanie; Trufa, Denis I.; Sı̂rbu, Horia; Finotto, Susetta

doi:10.4161/onci.22840

Cited by 31 publications

(27 citation statements)

References 69 publications

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“…This finding is of clinical relevance as there is growing interest in the use of TYK2 inhibitors for cancer therapy. 6,21,22 Nevertheless, kinase-inactive TYK2 does not fully reconstitute the WT situation and it is thus necessary to carefully consider the beneficial effects of TYK2 inhibitors versus their potential harmful effects on antitumor immunity. RMA-S 60 and RMA-Rae1 61 were cultured in RPMI1640 complete medium: RPMI1640 supplemented with L-glutamine (PAA), 10% heat-inactivated FCS (Invitrogen), 50 mM 2-mercaptoethanol (Gibco), 100 U/mL penicillin and 100 mg/ mL streptomycin (Sigma).…”

Section: Discussionmentioning

confidence: 99%

“…1 The most prominent immunological alterations observed in gene-targeted TYK2-deficient mice [2][3][4] and a naturally occurring TYK2 mutant mouse strain 5 are high susceptibility to microbial infections, resistance to several inflammatory and autoimmune diseases and impaired tumor immune surveillance. 1,6 Breast cancer, thymoma and colon adenocarcinoma transplants grow more progressively in Tyk2 ¡/¡ mice. [7][8][9] Similarly, TYK2 deficiency results in a higher incidence of Abelson-induced leukemia, which was attributed to an impaired NK cell cytotoxicity and NK cell-mediated tumor immune surveillance.…”

Section: Introductionmentioning

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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Section: Discussionmentioning

confidence: 99%

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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“…In cancer, the effects of TYK2 are similarly dichotomous. Although TKY2 is seemingly required for oncogenic fibroblast growth factor and epidermal growth factor signaling, TYK2 inhibition also appears to impede anticancer CD8 responses . Interestingly, in murine models of allografted thymoma cells, genetic deletion of TYK2 accelerated tumor development largely because of defects in CD8‐mediated cytotoxicity .…”

Section: Genotyping Results and Interpretation Of Molecular Resultsmentioning

confidence: 99%

Metastatic Thymoma Harboring a Deleterious BRCA2 Mutation Derives Durable Clinical Benefit from Olaparib

et al. 2019

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Thymomas comprise a group of rare epithelial neoplasms of the anterior mediastinum. Whereas localized disease carries a favorable prognosis, the majority of patients with metastatic thymomas experience progression or recurrence over a 10-year period. Although targeted therapies have become standard of care in many malignancies, no clinically actionable mutations have consistently been identified in metastatic thymomas.Here, we describe a patient with an aggressive thymoma complicated by extensive pleural metastases. Over a 16-year period, she progressed on multiple treatment regimens. To identify additional treatment options, tissue from a pleural metastasis was sent for next-generation sequencing, revealing mutations in BRCA2, tyrosine kinase 2, and SET domain containing 2. Based on supporting evidence for poly (ADP-ribose) polymerase (PARP) inhibition in other BRCA-mutated tumors, the patient was started on the PARP inhibitor olaparib. She derived significant clinical benefit from treatment, with imaging showing overall stabilization of her disease. Here, we review the genotyping results of her tumor and discuss the functional and clinical significance of the mutations in her cancer as well as implications for managing patients with advanced BRCA-mutant thymomas. The Oncologist 2020;25:301-305 KEY POINTS• Targeted therapy has yet to enter the standard clinical management of metastatic thymomas.• Patients with BRCA2-mutant thymomas may benefit from poly (ADP-ribose) polymerase inhibition.

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“…The conditional ablation of TYK2 uncovered the cell-intrinsic and -extrinsic requirements for TYK2 in the crosstalk between DCs, macrophages, and cytolytic effector cells. As the other JAK family members, TYK2 also has oncogenic properties: these are reviewed elsewhere [52,247,250].…”

Section: Discussionmentioning

confidence: 99%

TYK2 in Tumor Immunosurveillance

Karjalainen¹,

Shoebridge²,

Krunic³

et al. 2020

Cancers

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We review the history of the tyrosine kinase 2 (TYK2) as the founding member of the Janus kinase (JAK) family and outline its structure-function relation. Gene-targeted mice and hereditary defects of TYK2 in men have established the biological and pathological functions of TYK2 in innate and adaptive immune responses to infection and cancer and in (auto-)inflammation. We describe the architecture of the main cytokine receptor families associated with TYK2, which activate signal transducers and activators of transcription (STATs). We summarize the cytokine receptor activities with well characterized dependency on TYK2, the types of cells that respond to cytokines and TYK2 signaling-induced cytokine production. TYK2 may drive beneficial or detrimental activities, which we explain based on the concepts of tumor immunoediting and the cancer-immunity cycle in the tumor microenvironment. Finally, we summarize current knowledge of TYK2 functions in mouse models of tumor surveillance. The biology and biochemistry of JAKs, TYK2-dependent cytokines and cytokine signaling in tumor surveillance are well covered in recent reviews and the oncogenic properties of TYK2 are reviewed in the recent Special Issue ‘Targeting STAT3 and STAT5 in Cancer’ of Cancers.

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Establishing the role of tyrosine kinase 2 in cancer

Cited by 31 publications

References 69 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

Metastatic Thymoma Harboring a Deleterious BRCA2 Mutation Derives Durable Clinical Benefit from Olaparib

TYK2 in Tumor Immunosurveillance

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