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Review
. 2009 Nov;9(11):798-809.
doi: 10.1038/nrc2734.

STATs in cancer inflammation and immunity: a leading role for STAT3

Affiliations
Review

STATs in cancer inflammation and immunity: a leading role for STAT3

Hua Yu et al. Nat Rev Cancer. 2009 Nov.

Abstract

Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-kappaB (NF-kappaB) and interleukin-6 (IL-6)-GP130-Janus kinase (JAK) pathways, and by opposing STAT1- and NF-kappaB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy.

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Figures

Figure 1
Figure 1. STAT3 connects inflammation and cancer
Inflammation and cancer are linked by both oncogenic (intrinsic) and environmental (extrinsic) pathways. The intrinsic pathway is activated by genetic or epigenetic alterations in transformed cells. Such alterations include those that cause the overexpression or the persistent activation of growth factor receptors with intrinsic tyrosine kinase activity and cytokine receptors with associated Janus kinase (JAK) family tyrosine kinases. Oncogenic mutations in receptor-associated JAK family members also underlie some types of cancer. These receptors (several examples are shown), as well as non-receptor tyrosine kinases such as SRC, can be activated by extrinsic pathways — environmental factors that are associated with cancer inflammation — which include ultraviolet (UV) radiation, chemical carcinogens, infection, stress and cigarette smoke. Activated tyrosine kinases induced by both intrinsic and extrinsic pathways phosphorylate signal transducer and activator of transcription 3 (STAT3), which in turn forms dimers that translocate to the nucleus, where they directly regulate gene expression. In addition to upregulating numerous genes involved in proliferation, survival, invasion and metastasis, STAT3 induces the expression of many cytokines, chemokines and other mediators, such as interleukin-6 and cyclooxygenase 2, that are associated with cancer-promoting inflammation. Importantly, receptors for many of these cytokines, chemokines and mediators in turn further activate STAT3, thus forming autocrine and paracrine feedforward loops that result in a stable change to the genetic programme and the promotion of cancer inflammation. P, phosphorylation.
Figure 2
Figure 2. Different STAT proteins modulate pro-cancer and anti-tumour responses by myeloid cells
Myeloid cells, such as dendritic cells (DCs) and macrophages, can stimulate anti-tumour T helper 1 (TH1) adaptive immunity and even cause direct tumour cell death, which is associated with the production of TH1 cytokines, including interleukin-12 (IL-12) and interferon-γ (IFNγ). Activation of signal transducer and activator of transcription 1 (STAT1) (p-STAT1 denotes the activated phosphorylated form of STAT1) and STAT4 is important for anti-tumour TH1 responses. However, tumour-associated macrophages (TAMs) harbouring activated STAT3 (p-STAT3) no longer exhibit anti-tumour effects in the tumour microenvironment. Instead, along with myeloid-derived suppressor cells (MDSCs), TAMs promote cancer progression when STAT3 is activated. Moreover, STAT3 activity in the tumour microenvironment contributes to the expression of pro-cancer inflammatory mediators and angiogenic and growth factors, leading to increased tumour growth. Both activated STAT3 and STAT6 also promote MDSC expansion. Similar STAT3-dependent factors are produced by tumour cells and endothelial cells, forming a crosstalk network among tumour myeloid cells, tumour cells and tumour endothelial cells important for tumour angiogenesis and metastasis.
Figure 3
Figure 3. STAT proteins regulate cancer adaptive immunity
Signal transducer and activator of transcription 1 (STAT1) signalling in T cells promotes T helper 1 (TH1) differentiation and interleukin-12 receptor (IL-12R) expression. IL-12R signalling through STAT4 (p-STAT4 denotes the activated phosphorylated form of STAT4) further promotes TH1 expansion, which leads to interferon-γ (IFNγ) expression. In the TH1 milieu, adaptive immune responses control tumour growth. CD8+ T cells have a crucial role in cytotoxicity against tumour cells. Regulatory T (TReg) cells are important negative regulators of TH1 anti-tumour immunity. STAT5 is crucial for TReg cell differentiation and expansion. Both STAT5 and STAT3 contribute to the expression of forkhead box P3, a marker for TReg cells. At the same time, STAT3 activation in tumour TReg cells promotes the expression of IL-10 and transforming growth factor-β (TGFβ), which are the mediators of TReg cell suppressive functions, leading to the downregulation of TH1 anti-tumour immune responses. In the presence of increased IL-6, TGFβ and IL-23, all of which can be regulated by STAT3 in the tumour microenvironment, TH17 T cells expand and produce IL-17. This IL-17 activates STAT3 in diverse immune cells and other stromal cells in the tumour microenvironment through IL-6, which can further promote tumour growth.
Figure 4
Figure 4. Multilevel interactions between STAT3 and NF-κB
In normal physiology, nuclear factor-κB (NF-κB) is sequestered in the cytoplasm by inhibitor of NF-κBα (IκBα). When IκB kinases (IKKs) are activated by various pathogens and/or proinflammatory cytokines, IκBα is phosphorylated and degraded, allowing NF-κB nuclear translocation (BOX 1). As a transcription factor, NF-κB (especially REL) upregulates many genes involved in stimulating T helper 1 (TH1) immune responses that are necessary to control pathogens and to mediate anti-tumour immune responses. Several RELA downstream target genes encode factors that in turn activate signal transducer and activator of transcription 3 (STAT3) (TABLE 2). STAT3, which is also activated by intrinsic and extrinsic pathways, has the ability to inhibit IKK and thereby reduce NF-κB-associated TH1 immunity. In addition, STAT3 contributes to the persistent activation of NF-κB during chronic inflammation and in transformed cells by prolonging nuclear retention of RELA. NF-κB–IκBα complexes can shuttle in and out of the nucleus in the absence of stimuli, although the rate of nuclear export is greater than that of nuclear import. STAT3 facilitates nuclear localization of RELA through p300 (also known as EP300)-mediated acetylation, which interferes with the NF-κB–IκBα interaction and prevents their nuclear export. When STAT3 activity is increased in tumours, NF-κB prefers the STAT3–p300 interaction. Although their cognate DNA-binding sites need not be immediately adjacent, NF-κB and STAT3 regulate the expression of numerous oncogenic and inflammatory mediators (TABLE 2). Many of these gene products in turn further activate STAT3. Therefore, STAT3 and NF-κB interact at multiple levels, thereby promoting cancer inflammation, restraining anti-tumour TH1 immune responses and increasing tumour cell proliferation and survival as well as tumour angiogenesis and metastasis. P, phosphorylation; Ub, ubiquitylation.

References

    1. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–444. - PubMed

    1. Catlett-Falcone R, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 1999;10:105–115. This report was the first to document that IL-6–JAK–STAT3 signalling, which increases inflammation-induced cancer, is important for the growth and survival of human tumour cells.

    1. Bollrath J, et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell. 2009;15:91–102. - PubMed

    1. Kujawski M, et al. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J. Clin. Invest. 2008;118:3367–3377. This study demonstrated that STAT3 is a crucial mediator for myeloid cell-induced tumour angiogenesis.

    1. Kortylewski M, et al. Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell. 2009;15:114–123. - PMC - PubMed

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