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

Abstract

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...

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

“…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…”

“…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.…”

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

“…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).…”

STAT5 Loss Awakens the Dark Force in Natural Killer Cells

“…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.…”