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

Gotthardt, Dagmar; Putz, Eva Maria; Grundschober, Eva; Prchal-Murphy, Michaela; Straka, Elisabeth; Kudweis, Petra; Heller, Gerwin; Bagó-Horváth, Zsuzsanna; Witalisz-Siepracka, Agnieszka; Cumaraswamy, Abbarna A.; Gunning, Patrick T.; Strobl, Birgit; Müller, Mathias; Moriggl, Richard; Stockmann, Christian; Sexl, Veronika

doi:10.1158/2159-8290.cd-15-0732

Cited by 124 publications

(137 citation statements)

References 51 publications

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“…To further confirm activation of the IL-15 pathway, we evaluated STAT signaling in fresh peripheral blood NK cells by flow cytometry, because IL-15 signals through both STAT3 and STAT5. 25 There was a nonsignificant trend toward increased pSTAT3 expression and a significant upregulation of pSTAT5 in CTCL patients compared with normal donors ( Figure 2E). Overall, we propose a mechanism by which malignant CD4…”

Section: Resultsmentioning

confidence: 90%

“…The cause of this significant clinical relationship is unknown. Few recent studies have described the tumor-promoting potential of NK cells through their ability to upregulate certain oncogenic pathways such as VEGF-A, 25 mediated in part by reduced STAT5 activity. We described increased pSTAT5 and did not identify upregulation of VEGF-A or other immunosuppressive factors.…”

Section: Discussionmentioning

confidence: 99%

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Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma

Mundy-Bosse

Denlinger²,

McLaughlin³

et al. 2018

Blood Advances

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Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma

Mundy-Bosse

Denlinger²,

McLaughlin³

et al. 2018

Blood Advances

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“…Survival of STAT5-deficient NK-cells can be rescued by the enhanced expression of the anti-apoptotic gene Bcl-2 and allows studying the role of STAT5 for other NK-cell functions. STAT5 is not only regulating NK-cell survival, proliferation, and cytotoxicity but also drives cell maturation (94) by driving the expression of transcription factors involved in NK-cell maturation and survival (94). Besides allowing NK-cell maturation and cytotoxicity, STAT5 suppresses the tumor-promoting potential of NK-cells (94).…”

Section: The Good: Stat5: Teaches Nk-cells How To Drivementioning

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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“…In the study by Gotthardt and colleagues ( 7 ), in vitro treatment of murine or human NK cells with ruxolitinib, the fi rst JAK inhibitor approved by the FDA ( 4 ), which targets JAK1, JAK2, and JAK3 upstream of STATs, greatly enhanced expression of Vegfa . Most importantly, larger tumors were observed in control mice bearing v-abl + tumors after injection of ruxolitinib compared with Vegfa Δ / Δ Ncr1 -iCre Tg mice.…”

Section: Ncr1 -Icrementioning

confidence: 99%

STAT5 Loss Awakens the Dark Force in Natural Killer Cells

Cerwenka

2016

Cancer Discovery

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Summary: Natural killer cells (NK) are commonly considered to be potent antitumor effector cells. The study by Gotthardt and colleagues challenges this concept and reveals that STAT5-defi cient/inhibited NK cells induce angiogenesis and promote tumor progression. These unexpected fi ndings shed new light on potential adverse effects of JAK-STAT inhibitors in the clinics. Cancer Discov; 6(4); 347-9. ©2016 AACR . Gotthardt et al., p. 414 (7). See related article byWithin the tumor microenvironment the interaction of tumor cells and immune cells critically shapes the progression of malignant disease ( 1 ). There is now increasing evidence that certain types of immune cells have the potential not only to effi ciently control, but also to promote tumor growth. For instance, M1 macrophages in tumors can directly kill tumor cells, whereas M2 macrophages support tumor angiogenesis and tumor development. So far, natural killer (NK) cells that effi ciently lyse tumor cells and produce infl ammatory cytokines such as IFN γ and TNF α are mainly associated with potent antitumor activity. Individuals with high NK cell activity have a lower risk to develop cancer ( 2 ). NK cell infi ltration in the tumor is frequently correlated with improved prognosis for patients with cancer, and in many mouse tumor models depletion of NK cells leads to accelerated tumor growth ( 1 ). These studies imply an important role of NK cells in tumor immunosurveillance and support clinical application of NK cell-based therapies in the clinic for cancer treatment. More recently, additional immunoregulatory functions have been attributed to NK cells. In infectious disease, NK cells were shown to kill activated T cells and to produce IL10 and TGF β , resulting in the downregulation of immune responses. Accordingly, a recent study revealed that high numbers of tumor-infi ltrating NK cells did not correlate with favorable prognosis and even might promote tumor progression ( 3 ). The mechanisms underlying NK cell-mediated tumor progression are poorly understood. Moreover, the molecular switches determining NK cell-mediated antitumor or protumor activity have not been elucidated. Strategies to counteract the potential tumor-promoting activity of NK cells could improve current NK cell-based antitumor therapies.The JAK-STAT pathway is activated in many tumor cells and promotes tumor progression. JAK-STAT inhibitors have been extensively explored for cancer treatment, and more than 20 JAK-STAT inhibitors are being tested in clinical trials ( 5 ). The JAK-STAT pathway is also critical for lymphocyte activation, for instance by the cytokines IL2, IL12, IL15, and IL18 that mediate NK cell activity and/or development. Accordingly, NK cells from patients with myeloproliferative neoplasm treated with a JAK inhibitor show impaired functional activity ( 5 ). A previous study by the Sexl lab ( 6 ) Δ / Δ Ncr1 -iCre Tg -Vav-Bcl2 mice showed severe functional defects in vitro , including impaired proliferation and decreased cytotoxicity and IFN γ production toward tumor...

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

Cited by 124 publications

References 51 publications

Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma

Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma

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

STAT5 Loss Awakens the Dark Force in Natural Killer Cells

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