Abstract B39: Regulation and function of IL-1b in immune modulation of pancreatic cancer

Abstract

Abstract Pancreatic intraepithelial neoplasms (PanINs) are well-defined precursor lesions of pancreatic ductal adenocarcinoma (PDA). The initiation and progression of PanINs is marked by dynamic stromal reconstruction and localized acute inflammation. Using an orthotopic transplantation model of early and advanced pancreatic neoplasia in immunocompetent recipient mice, we have uncovered a crucial role for the cytokine IL-1b in KRasG12D-driven PanIN evolution. Tumor cell-derived IL-1b¢ was found to be critical for shaping the protumorigenic PanIN microenvironment by promoting activation of quiescent pancreatic stellate cells and establishing an immunosuppressive milieu mediated by M2 macrophages, MDSCs and CD1dhiCD5+ regulatory B cells. Furthermore, loss of IL-1 signaling in tumor stroma activates the cytotoxic T-cell immune response, significantly attenuates PanIN growth and confers survival advantage to PDAC-bearing mice. Tumor cell expression of IL-1b in vivo is driven by upregulation of TLR4 signaling and activation of the NLRP3 inflammasome. KrasG12D enhances surface TLR4 expression, sensitizing transformed cells to TLR4 ligands in the microenvironment, including the pancreatic microbiome. Collectively, our study describes a complex tumor-stromal interplay orchestrated by the TLR4-NLRP3-IL-1b signaling axis, which is critical for shaping the tumor microenvironment and driving pancreatic tumorigenesis. Citation Format: Shipra Das, Sandra Vogt, Christina Hadju, Dafna Bar-Sagi. Regulation and function of IL-1b in immune modulation of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B39.