Constitutive STAT3 activation in glioblastoma multiforme impairs anti-tumor immunity and production of pro-inflammatory cytokines. Free

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Glioblastoma multiforme (GBM) is the most common brain malignancy and has a devastating clinical outcome. GBM patients have a very poor prognosis, with mean survival time of approximately one year after diagnosis, and only 2% survival at three years. The poor prognosis is attributed, at least in part, to constitutive activation of intracellular signal transduction proteins, including PI-3 kinase/Akt, mTor, MAP kinases, and signal transducers and activators of transcription (STATs), which are known to support GBM cell survival and proliferation, and resistance to anti-cancer therapies. The role of these signaling molecules in the regulation of anti-tumor immune responses, on the other hand, is poorly understood. In the present study, we have identified a function for STAT3 in negative regulation of anti-tumor immunity to GBM. Expression of a dominant negative (DN) allele of STAT3 (Y705F) enhanced lysis of U87 GBM cells by human IL-2-activated peripheral blood mononuclear cells (PBMCs), and increased production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-a and interferon gamma (IFN-g). Conversely, expression of a constitutively active (CA) STAT3 mutant (STAT3C) in U87 reduced the production of pro-inflammatory cytokines and blocked anti-tumor cytotoxicity by immune effectors. Our results suggest that constitutive activation of STAT3 in GBM has a dual function: it (i) enhances tumor cell proliferation and survival, and (ii) promotes immune evasion by impairing host anti-tumor immune responses.