Loss of STAT3 in Lymphoma Relaxes NK Cell-Mediated  Tumor Surveillance

Putz, Eva Maria; Hoelzl, Maria A.; Baeck, Julia; Bagó-Horváth, Zsuzsanna; Schuster, Christian; Reichholf, Brian; Kern, Daniela; Aberger, Fritz; Sexl, Veronika; Hoelbl-Kovacic, Andrea

doi:10.3390/cancers6010193

Cited by 14 publications

(10 citation statements)

References 66 publications

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“…STAT transcription factors may induce or repress transcription and have been implicated in NK cell development and function44. JAKs are stably associated with cytokine receptors and induce the activation of STATs upon receptor stimulation, with STAT5 being predominantly activated by IL-2, IL-7, and IL-1545.…”

Section: Discussionmentioning

confidence: 99%

Suppressor of Cytokine Signaling 2 Negatively Regulates NK Cell Differentiation by Inhibiting JAK2 Activity

Kim

et al. 2017

Sci Rep

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Suppressor of cytokine signaling (SOCS) proteins are negative regulators of cytokine responses. Although recent reports have shown regulatory roles for SOCS proteins in innate and adaptive immunity, their roles in natural killer (NK) cell development are largely unknown. Here, we show that SOCS2 is involved in NK cell development. SOCS2−/− mice showed a high frequency of NK cells in the bone marrow and spleen. Knockdown of SOCS2 was associated with enhanced differentiation of NK cells in vitro, and the transplantation of hematopoietic stem cells (HSCs) into congenic mice resulted in enhanced differentiation in SOCS2−/− HSCs. We found that SOCS2 could inhibit Janus kinase 2 (JAK2) activity and JAK2-STAT5 signaling pathways via direct interaction with JAK2. Furthermore, SOCS2−/− mice showed a reduction in lung metastases and an increase in survival following melanoma challenge. Overall, our findings suggest that SOCS2 negatively regulates the development of NK cells by inhibiting JAK2 activity via direct interaction.

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Section: Discussionmentioning

confidence: 99%

Suppressor of Cytokine Signaling 2 Negatively Regulates NK Cell Differentiation by Inhibiting JAK2 Activity

Kim

et al. 2017

Sci Rep

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“…Sections (3 μ m) were stained with hematoxylin/eosin according to standard histologic procedures. CD31 (Cell Signaling; #9654S) stainings were performed as previously reported ( 49 ). The stainings were scanned and photographed with an Olympus IX71 or a Nikon Eclipse E1000 microscope using cellSens Dimension (Olympus) or NIS-elements (Nikon) software.…”

Section: Histologymentioning

confidence: 99%

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

et al. 2016

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Natural killer (NK) cells are tightly regulated by the JAK-STAT signaling pathway and cannot survive in the absence of STAT5. We now report that STAT5-defi cient NK cells can be rescued by overexpression of BCL2. Our experiments defi ne STAT5 as a master regulator of NK-cell proliferation and lytic functions. Although NK cells are generally responsible for killing tumor cells, the rescued STAT5-defi cient NK cells promote tumor formation by producing enhanced levels of the angiogenic factor VEGFA. The importance of VEGFA produced by NK cells was verifi ed by experiments with a conditional knockout of VEGFA in NK cells. We show that STAT5 normally represses the transcription of VEGFA in NK cells, in both mice and humans. These fi ndings reveal that STAT5-directed therapies may have negative effects: In addition to impairing NK-cell-mediated tumor surveillance, they may even promote tumor growth by enhancing angiogenesis. SIGNIFICANCE:The importance of the immune system in effective cancer treatment is widely recognized. We show that the new signal interceptors targeting the JAK-STAT5 pathway may have dangerous side effects that must be taken into account in clinical trials: inhibiting JAK-STAT5 has the potential to promote tumor growth by enhancing NK-cell-mediated angiogenesis. Cancer Discov; 6(4); ©2016 AACR . Ni and Cerwenka, p. 347. See related commentary by INTRODUCTIONNatural killer (NK) cells are innate lymphocytes that develop from a common lymphoid progenitor in the bone marrow ( 1 ). They represent the fi rst line of defense against infected, stressed, and malignant cells. Recent evidence has assigned distinct features and functions to tissue-specifi c NK cells ( 2 ). NK cells have organ-specifi c properties, such as distinct profi les of receptor expression or cytokine production ( 3 ). Uterine NK cells secrete high levels of VEGFA and are involved in placental vascularization. The physiologic functions of other organ-specifi c NK-cell subsets are less well understood ( 4 ). STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor PromotionDagmarAll aspects of NK-cell development are regulated by cytokines, their downstream signaling pathways, and transcriptional regulators. These include key cytokines such as IL2, IL12, IL15, IL18, and IL21 ( 5 ), most of which signal via the common γ chain ( 5 ) and activate the JAK-STAT pathway ( 6 ). JAK kinases (JAK1-3 and TYK2) bind to cytokine receptors and are activated by ligand/receptor binding. The activated kinase phosphorylates STAT transcription factors refs. 6,7 ).Consistent with its function as the major STAT protein downstream of IL7, IL2, and IL15, STAT5 is absolutely essential for conventional NK-cell development and survival; Stat5 Δ / Δ Ncr1-iCre Tg mice lack NK cells ( 8 ). It is also important for lymphoid cell development ( 9 ): STAT5 is constitutively active in a plethora of lymphoid malignancies ( 10 ). Recent studies have described somatic Stat5b mutations as active drivers of lymphoid mali...

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“…1 STAT transcription factors may induce or repress transcription and have been implicated in natural killer (NK) cell development and function. [2][3][4][5][6] STAT1 is known to regulate NK cell cytotoxicity and cytokine production. 5,7 STAT4 is highly expressed in resting NK cells and regulates interferon-g (IFN-g) production upon interleukin-12 (IL-12) stimulation by activating the T-box transcription factor T-bet.…”

Section: Introductionmentioning

confidence: 99%

“…13 As a result, NK cell functions may be altered: inhibitory as well as activating effects have been reported. [2][3][4] Inhibiting STAT3 is a potential approach for treating various forms of cancer. However, our knowledge of STAT3's role in NK cells is limited.…”

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confidence: 99%