The role of STAT3 in immune surveillance of cancer

STAT proteins are latent transcription factors that mediate cytokines and growth factors initiated transcription. Many oncogenes are found to be able to activate STAT3 proteins to transform cells while aberrant constitutive STAT3 activation has been found in more than 50% of different human and murine primary tumors and transformed cell lines, indicated its imperative role in tumor evasion of immune surveillance. We find out that constitutive STAT3 activation in tumor cells not only suppresses tumor expression of pro-inflammatory mediators but also induces production of factors that inhibit functional differentiation of dendritic cells (DCs). Interrupting STAT3 signaling in tumor cells enhances expression of several pro-inflammatory cytokines and chemokines that activate cellular components of innate and adaptive immunity including DCs, resulting in stimulation of antigen-specific T cells both in vitro and in vivo. Conversely, transformation of 3T3 fibroblasts by v-Src, which signals through STAT3, or by enforcing expression of a constitutively activated STAT3 protein, STAT3C, inhibits the expression of induced pro-inflammatory mediators. Another mechanism transformed cells could utilize to evade immune surveillance and possibly induce immune tolerance is by elaborating factors that inhibit DC differentiation/maturation from progenitor cells. We show here that transformation by either v-Src or STAT3C induces the elaboration of factors that inhibit functional differentiation/maturation of dendritic cells, one of which is the angiogenesis factor VEGF. Moreover, in vivo disrupting STAT3 signaling in tumor cells induced the infiltration of immunological cells, including macrophages, neutrophils as well as T cells. Finally, tumor cells with disrupted STAT3 signaling could elicit stronger tumor antigen-specific immune activity in vivo. Therefore, STAT3 not only affects cell cycle and apoptosis but also functions as a negative regulator involved in the suppression of immune system.; Our findings thus suggest that immune evasion can occur at the early stages of cancer development because transformation by constitutive Stat3 activity inducible by numerous prevalent oncogenic events inhibits both the production and sensing of inflammatory signals critical for eliciting innate and adaptive immunity.