As tumors develop and progress, they disrupt surrounding tissues through direct invasion and distant tissues through metastases. These processes are intrinsically proinflammatory and thus have the potential to induce anti-tumor immune responses directed against tumor specific antigens. In this fashion, the immune system can act as an extrinsic tumor suppressor. We have hypothesized that tumors must actively develop mechanisms to suppress the release and sensing of these immunologic danger signals in order to survive and propagate without inciting anti-tumor immunity. Along these lines, we have demonstrated that the oncogenic Stat3 signaling pathway, which is constitutively activated in over 50% of diverse cancers, may serve such a role. In transplantable tumor models with constitutively activated Stat3, inhibition of Stat3 signaling results in the release of proinflammatory cytokines and chemokines as well as factors, such as VEGF and IL10, which inhibit DC maturation. Recently, we have further derived evidence that tumor induced Stat3 signaling in multiple hematopoietic cell types restrains tumor immune surveillance, defining a potential second level through which Stat3 signaling inhibits the generation of antitumor immunity. These findings suggest that Stat3 may be an interesting target for inhibition to enhance antitumor immunity. The role of Stat3 signaling has not yet been studied in endogenously arising cancer models. In the current proposal, we will use both genetic and pharmacologic approaches to evaluate the role of Stat3 signaling in blocking antitumor immunity in endogenously arising tumors from our autochthonous transgenic models of prostate and breast cancer as well as the potential for inhibition of Stat3 alone and in combination with vaccines and other agents to enhance therapeutic anti-tumor immunity. Specifically, we propose to: 1)Evaluate the role of tumor Stat3 signaling on prostate/prostate cancer specific immunity and tolerance in the ProHAxTRAMP autochthonous prostate cancer model, 2)Evaluate the role of hematopoietic Stat3 signaling on prostate/prostate cancer specific immunity and tolerance in the ProHAxTRAMP autochthonous prostate cancer model and breast cancer specific immunity and tolerance in the MMTV-Her2 autochthonous breast cancer model, 3)Evaluate the role of Stat3 signaling on the expression of B7-H1 and B7-H4 on tumor and other cellular elements of the tumor microenvironment and 4) Evaluate the capacity of a small molecule Stat3 inhibitor, CPA-7, to inhibit Stat3 signaling in tumor and infiltrating hematopoietic cells and subsequent enhancement of therapeutic anti-tumor immunity. ? ? ?
