Abstract 1188: IL-17/IL-17RA signaling in the pancreatic epithelium upregulates B7-H4 to promote tumorigenesis

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is expected to overtake other cancers as the second leading cause of death from cancer. PDAC is distinguished by the early formation of a highly immunosuppressive fibro-cellular tumor microenvironment (TME). Our group has demonstrated that IL-17 is necessary for the development and spread of pancreatic cancer, but we have not yet identified the cellular compartment responsible for IL-17-mediated tumor promotion. We propose that early pancreatic carcinogenesis is mediated by modification of an immunosuppressive program and is dependent on pancreatic epithelial IL-17/IL-17RA signaling. We created mice with Kras activated and IL-17RA selectively deleted from the pancreatic compartment (KC; IL-17RAfl/fl). In order to specifically remove IL-17RA from hematopoietic cells, we implanted IL-17RA deficient (IL17-RA−/−) bone marrow cells into KC animals. While deletion of IL-17RA in the hematological compartment had no effect on the progression of pancreatic carcinogenesis, deletion of IL-17RA from the epithelial compartment delayed the development of premalignant lesions, indicating that the pancreatic epithelium is the compartment required for IL-17/IL-17RA signaling during tumorigenesis. Deletion of IL-17RA from the oncogenic epithelium resulted in increased cytotoxic CD8+T cells infiltration in the TME. To learn more about the transcriptional alterations brought on by the lack of IL-17RA in the pancreatic compartment we performed single cell sequencing of pancreas tissue of KC and KC; IL-17RAfl/fl. We found that the absence of IL-17RA in the pancreatic compartment had an impact on epithelial cells transcriptional profiles, with modulation of several immune pathways including regulation of B7-H4, a negative regulator of T cells through Eomes activation. We have generated pancreatic cancer transgenic animals that lack B7-H4 and found that KC; B7-H4−/− mice have delayed tumorigenesis and decreased immunosuppression. In sum, we describe a novel IL-17-mediated regulation of B7-H4 and unravel its function in pancreatic tumorigenesis. Citation Format: Susana Castro Pando, Le Li, Rian Morgan Howel, Marilina Mascaro, Olivereen Le Roux, David Romanin, Erick Riquelme, Yu Zhang, Jay Kolls, Seyed Javad Moghaddam, Florencia McAllister. IL-17/IL-17RA signaling in the pancreatic epithelium upregulates B7-H4 to promote tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1188.