The authors found that blocking Stat3 activation in the B16 mouse tumour cell line — by expressing Stat3β, dominant-negative Stat3, or using antisense oligonucleotides — increased expression of the pro-inflammatory cytokines interferon-β, tumour-necrosis factor-α (Tnf-α) and interleukin-6 (Il-6), and the chemokines Rantes and Cxcl10. By contrast, fibroblasts that were engineered to constitutively express Stat3 failed to express Il-6 or Rantes after stimulation with inflammatory mediators, confirming that Stat3 activation inhibits expression of cytokines and chemokines. So, exactly how does Stat3 activation in tumour cells affect the immune response?
There are two components of the immune response — innate and adaptive. Cytokines and chemokines amplify pro-inflammatory signals that are involved in the innate immune response. Blocking tumour-cell expression of Stat3 in vitro strongly induced Rantes and nitric-oxide production by macrophages, and Tnf-α production by neutrophils. Similar effects were seen in vivo, as disruption of Stat3 signalling by gene transfer of Stat3β into B16 tumours resulted in immune-cell infiltration. Innate immunity is crucial for the development of adaptive immunity, as it enhances maturation of DCs. As expected, DCs that were cultured with supernatants from Stat3β-expressing B16 cells — but not controls — increased levels of DC maturation markers. In addition, DCs that were exposed to supernatants from Stat3-inhibited B16 cells had increased proliferation of and cytokine release by antigen-specific T cells. Again, these observations were confirmed in vivo, as interruption of Stat3 signalling in B16 tumour cells caused infiltration and activation of tumour-specific CD8+ T cells. Stat3 activation in tumour cells therefore blocks expression of inflammatory mediators, which are required to activate both arms of the immune system.
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