Abstract 4575: IL17 signaling modulates tumor microenvironment in pancreatic cancer

Abstract

Abstract Pancreatic cancer is the one of the most devastating malignancies and the 5-years survival remains below 10% for decades. The pancreatic tumor microenvironment is very complex with tumor cells surrounded by a dense fibro-inflammatory stroma with fibroblasts and immune-suppressive cells which are known to play a pivotal role in the whole process of tumorigenesis, and contributing to the lack of responses to most therapies. We have previously described that IL17, a cytokine secreted from immune cells recruited to the pancreas in response to Kras and inflammation, is involved in the initiation and development of pancreatic premalignant lesions, in part by promoting stemness on the oncogenic epithelium. In this study, we aim to dissect the role of IL17 on the stroma in established pancreatic adenocarcinoma. To this end, we blocked the IL17 signaling pathway with monoclonal antibodies and also used a parallel genetic approach which consisted in IL17RA deletion from the cancer cells using CRISPR-Cas9. RNA sequencing analysis, flow cytometry, immunohistochemistry, and opal-multiplex immunofluorescence were performed on tumors and cellular compartments. We uncovered that neutrophils recruitment was the main pathway altered by IL-17. Using flow cytometry, IHC and opal-multiplex we found that Gr1+ cells were significantly modulated by Il17 in the tumor microenvironment, as not only the numbers of these cells were altered but also their spatial distribution with respect to CD8+T cells, which may contribute to the generation and maintenance of the immunosuppressive microenvironment that characterizes pancreatic cancer. Moreover, we found that reactive oxygen species (ROS) level was also evidently downregulated by IL17 signaling blockage.Therefore, we conclude that IL17 plays an important role in remodeling the pancreatic cancer immunosuppressive tumor microenvironment. Citation Format: Yu Zhang, Erick Marcelo Riquelme Sanchez, Michelle Annabel Zoltan, Florencia McAllister. IL17 signaling modulates tumor microenvironment in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4575.