Regulation and role of fibroblast-derived interleukin-33 in the pancreatic tumor microenvironment

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is a highly deadly disease with a five-year survival rate of only 10%. The bulk of the PDA tumor volume is composed of a reactive fibroinflammatory tumor microenvironment that assists in the growth and maintenance of the tumor. The highly immunosuppressive nature of the pancreatic tumor microenvironment is also responsible, in part, for the continued inefficacy of immunotherapy treatments in PDA patients. Despite numerous studies that have previously examined different facets of PDA immunosuppression, there is still much that is unknown regarding the complex network of intercellular crosstalk that regulates this phenomenon. Our previous work has demonstrated that infiltrating macrophages are essential mediators of immunosuppression in PDA, and that their polarization is affected by the expression of oncogenic Kras in tumor cells. Other groups have characterized the immunosuppressive impact of certain fibroblast subgroups within the pancreatic tumor microenvironment. Preliminary experiments described in this proposal demonstrate a connection between fibroblasts, macrophages, and tumor cells through fibroblast expression of the cytokine interleukin-33 (IL33). The role of IL33 in cancer biology is controversial, with its overall effect on the tumor thought to be supportive or suppressive depending on the cancer context. Here, results show that IL33 abundance correlates with disease progression and that fibroblast expression of IL33 is dependent on oncogenic Kras-driven signals from tumor cells. Additionally, we have completed a pilot experiment whereby we have orthotopically implanted pancreatic tumor cells into a syngeneic genetically engineered mouse model lacking Il33 in fibroblasts (Il33f/f, Pdgfra-CreERT2/+). Tumors from Il33-deficient mice had slower tumor growth and a trending decrease in macrophage infiltration, suggesting that fibroblast-derived Il33 is both tumor promoting and may play a role in the recruitment of immunosuppressive macrophages. Therefore, the overall objective of this study is to elucidate the cellular interactions that contribute to the establishment and maintenance of immunosuppression in PDA, and the central hypothesis is that fibroblast derived IL33 is a key regulator of immunosuppression in the pancreatic tumor microenvironment through its modulation of macrophage infiltration. This hypothesis will be investigated through the following two Aims: (Aim 1) define the regulation and role of IL33 in cancer-associated fibroblasts, and (Aim 2) assess the impact of IL33 on the recruitment of tumor-associated macrophages. To complete this investigation, a combination of in vitro assays using tumor cell, fibroblast, and macrophage cultures will be performed. We also will continue to utilize the Il33f/f, Pdgfra-CreERT2/+ genetically engineered mouse model to assess Il33-dependent changes in the immunosuppressive nature of pancreatic tumors. The data accumulated by this study will further the field’s understanding of immunosuppression regulation in PDA, and consequentially bring effective immunotherapy strategies one step closer to becoming a viable therapeutic option.