The first study demonstrating Stat3 as a negative regulator of Thl-type immune responses reported that ablation of Stat3 in neutrophils and macrophages increased production of Thl cytokines, such as IFNg, TNFa, and IL-1, after LPS stimulation (Takeda et al. 1999). A role of Stat3 in inhibiting immunostimu-latory Thl cytokines and other mediators in tumors was subsequently shown (Nabarro et al. 2005; Sumimoto et al. 2006; Wang et al. 2004). Because of Stat3 is a critical oncogenic molecule, a direct link between oncogenesis and tumor immune evasion was thus substantiated. Further studies revealed that Stat3 activation in immune cells is in part mediated by tumor-derived factors, such as VEGF, IL-10, and IL-6 (Sumimoto et al. 2006; Wang et al. 2004). Conversely, Stat3 ablation in immune cells leads to induction of Thl mediators involved in both innate and T-cell-mediated adaptive immunity. In turn, this causes increased anti-tumor activity of immune cells that impedes tumor progression (Kortylewski et al. 2005) (Fig. 1).
Many of the Th1 mediators produced in tumors upon Stat3 ablation are typical targets of other immune regulators, such as NF-kB and/or Stat1, whose role is pivotal in Th1-mediated immune responses (Yu et al. 2009). Deletion of Stat3 facilitates activation of NF-kB (Welte et al. 2003) and Stat1 (Takeda et al. 1999), leading to increased production of Th1 type immune mediators required for antitumor immunity (Kortylewski et al. 2009c; Yu et al. 2009). Although various mechanisms have been suggested, how Stat3 antagonizes NF-kB and Stat1 remains to be further defined. It has been implicated from several studies that Stat3 negatively regulates IkB kinase ß (IKKß), which is required for phosphorylation of IkBa and its subsequent degradation (Lee et al. 2009; Welte et al. 2003). This may render NF-kB in a suppressed state, keeping it from activating downstream genes involved in Th1 type immune responses. However, a synergistic interaction between Stat3 and NF-kB is also documented during tumor progression through autocrine/parcrine signaling of IL-6 and IL-10 (Bollrath et al. 2009; Grivennikov et al. 2009; Lam et al. 2008; Lee et al. 2009). Distinct from the interaction between Stat3 and NF-kB, Stat3 and Stat1 often oppose each other in cancer models - if Stat3 is highly activated, Stat1 is downregulated. In the setting of melanoma, it has been noted that increased expression of activated Stat1 is an important predictor of therapeutic responsiveness to interferon-a (IFNa) (Lesinski et al. 2007; Wang
Fig. 1 Multifaceted role of Stat3 in anti-tumor immunity. Stat3 is persistently activated in tumors and the tumor microenvironment, inducing production of many tumor-derived factors such as VEGF, IL-10, and IL-6. Increased Stat3 activity in tumor-associated immune cells promotes immunosuppressive environment, by mediating the generation of immune suppressor cells, including MDSC and T regs. The expression of MDSC and Treg effector molecules, such as TGF-ß, IL-10, and IL-23, is in part mediated by Stat3. Activated Stat3 in tumor-associated immune cells also inhibits DC maturation as well as the production of Th1-type cytokines such as IL-12 and IFN-g. As such, Stat3 activity in tumor impairs both adaptive and innate immune responses against tumor
Tumor l IFNß l RANTES
l IFNY l MHCII Stat3P+ lIL-12 l CD80
VEGF IL-10 IL-6
l IP-10 l STAT1
Immunosuppression et al. 2007; Zimmerer et al. 2007) and correlates with longer overall survival (Wang et al. 2007). These studies suggest that the balance between Stat1 and Stat3 may determine the therapeutic outcome of cancer immunotherapy and targeting Stat3 may shift cellular balance more favorable toward host. It has recently been noted that single nucleotide polymorphism associated with Stat3 expression may be a significant predictor of IFNa response. In a study of 174 patients with chronic myelogenous leukemia (CML), the single nucleotide polymorphism (SNP) rs6503691 was tightly correlated with the level of STAT3 mRNA, and could further reliably distinguish responders and non-responders to IFN-a (Kreil et al. 2010). In a separate assessment of 75 patients with metastatic renal cell carcinoma (mRCC) treated with IFN-a, it was documented that the rs4796793 polymorphism in the 5' region of Stat3 was a significant predictor of clinical response (odds ratio [OR] = 2.73, 95% CI 1.38-5.78) (Ito et al. 2007). The enhanced growth inhibitory effects of IFNa upon Stat3 suppression in renal cell carcinoma also supports the notion that Stat3 inhibition is a useful tool to boost the efficacy of IFNa therapy in patients with renal cell carcinoma.
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