Abstract The incidence of pancreatic adenocarcinoma (PDAC) is steadily increasing while most treatment modalities remain ineffective. Therefore, it would not be a surprise to learn that PDAC is one of the top-4 causes of cancer- related mortality. What is most striking about this malignancy is that even if detected at early stages, outcomes remain poor. It is well known that pancreatic cancer is characterized by an immunosuppressive environment, already found surrounding premalignant lesions or pancreatic intraepithelial neoplasia (PanIN), which has been postulated as one of the main reasons for the lack of response to most therapies. However, the regulatory signals that precede and support the development of this suppressive TME are not well characterized. The objective of this grant is to characterize the mechanisms and regulators implicated in the generation of the immunosuppressive TME that characterizes pancreatic tumorigenic process and to reverse it through pharmacological and microbial interventions. Our laboratory found that IL-17-secreting immune cells play an important role in promoting pancreatic tumorigenesis in genetically engineered mouse (GEMM) models of pancreatic cancer. We now plan to characterize the mechanisms by which IL-17 promotes tumorigenesis by genetically deleting the IL-17 receptor specifically from the pancreatic oncogenic epithelium using GEMM and CRISPR/Cas9 (Aim 1). We also found that IL-17 neutralization decreases recruitment of myeloid cells, mostly neutrophils, and induces CD8+T cells activation and in PDAC orthotopic model. Monoclonal antibodies against IL-17 or neutrophils will be used to assess the mechanisms employed by IL-17 supporting an immunosuppressive TME (Aim 2). Finally, we have recently found that fecal microbial transplants can modulate tumors systemically. In particular, human PDAC-associated gut bacteria is capable of increasing IL-17 levels in circulation, which may affect distant tumors like pancreatic cancer. We now plan to definitively address the role gut bacteria in promoting Th17 differentiation and its systemic implications by performing human-into-mice fecal microbial transplants (Aim 3). Achieving our goals will not only help us better understand immunological as well as microbial mechanisms implicated in pancreatic tumorigenesis, but will also result in practical novel interventions with either monoclonal antibodies, narrow spectrum antibiotics or microbial transplants that would have a direct impact in preventing and/or treating this deadly disease.