Our laboratory has recently pioneered a novel cancer gene therapy based on blocking Stat3 signaling, which is constitutively-activated in numerous human cancers and murine tumor cells. The relevance of this approach to human cancer is validated by growth inhibition/apoptosis in vitro of many cancer cells when their constitutively activated Stat3 signaling pathway is interrupted. In vivo gene therapy to block Stat3 signaling results in massive tumor cell death, involving a significant killing of genetically untransduced tumor cells. Our recent studies demonstrate that blocking Stat3 signaling in tumors induces heavy infiltration of macrophages, neutrophils and T cells. In vitro studies suggest that infiltration of immune cells in tumors is triggered by soluble factors produced by tumor cells upon blocking constitutive Stat3 signaling. The tumor cell-produced soluble factors are capable of activating innate immune cells to produce additional immunogenic signals and tumoricidal effectors, including nitric oxide and TNF-a. We further demonstrated that interruption of constitutive Stat3 signaling induces the expression of pro-inflammatory cytokines and chemokines such as IL-6, TNF-a, IFN-beta, RANTES and IP-10 by tumor cells. Significantly, blocking Stat3 signaling in murine B 16 tumor cells in vivo leads to systemic activation of macrophages, IFN-g secreting cells and tumor antigen (TRP-2)-specific CD8+ T cells. The cascade of pro-inflammatory signals that lead to innate and adaptive antitumor immune responses by a Stat3 blockade is highly reminiscent of a pathogen-induced danger signal cascade critical for the induction of anti-pathogen immune responses. Thus, interrupting constitutive Stat3 signaling in tumors offers a unique opportunity to learn how the pro-inflammatory signals released by tumors alert and arm the immune system to fight against cancer cells. The central hypothesis to be tested in this proposal is that innate and T cell immune responses, initiated by pro-inflammatory signals produced by tumor cells upon blocking Stat3 signaling, are important for the antitumor efficacy of targeting Stat3. To test this hypothesis, we will validate in vivo the tumoricidal effects of innate immune cells activated by the pro-inflammatory signals described above. We will also determine the role of T cell-mediated antitumor immune responses in anti-Stat3 antitumor therapy. Finally, we will define the cellular and molecular mechanisms by which innate immune responses triggered by tumor-released pro-inflammatory factors impact on tumor-specific adaptive immune responses.
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