Abstract
Abstract Introduction: Persistent inflammation due to alcoholic chronic pancreatitis (ACP) is associated with pancreatic ductal adenocarcinoma (PDAC). Myeloid cell infiltration within the pancreas, particularly with oncogenic mutant KrasG12D/+ (*Kras), is crucial for driving PDAC carcinogenesis. Our previous work demonstrated that hyperactivation of cyclic AMP response element binding protein (CREB) accelerates ADM/PanIN progression with heightened fibroinflammation. However, the association between CREB in precursor neoplastic lesions and innate myeloid cells remains unclear. Methods: We established an ACP mouse model using an alcohol diet along with prolonged caerulein administration in Ptf1aCreERTM/+; LSL-KrasG12D/+ (KC), and CREB deleted [Crebfl/fl in KC (KCC-/-)] mice. Single-cell RNA sequencing (scRNA-seq) of the mouse pancreas, multiparametric immunophenotyping of tumor-infiltrating myeloid cells and chromatin immunoprecipitation (ChIP-seq) with CREB pulldown were performed. Cytokine arrays and qPCR studies followed co-culture assays using mouse neutrophils (J774M) and macrophages (RAW 264.7) with epithelial cell lines harboring *Kras with in vitro ACP induction were conducted. Results: ACP induction in KC mice led to increased infiltration of neutrophils and alternatively activated macrophages with the pancreas. Conversely, Creb-deleted mice exhibited significantly reduced myeloid cell infiltration despite ACP induction. ChIP-Seq and qPCR identified CREB-regulated chemokines and immunomodulators as mediators of myeloid cell trafficking. Co-culture of mouse neutrophils and macrophages with KC-ACP conditioned media significantly increased IL-1 receptor antagonist (Il-1ra) expression and secretion. Single-cell transcriptomic analysis revealed heightened Il1rn mRNA levels in neutrophils and macrophages in KC-ACP when compared with KC pancreatic tumors. Creb-deleted PDAC models showed strong downregulation of Il1rn in macrophages, confirming CREB’s role in modulating myeloid cell interactions via epithelial cell signaling. Conclusions: Our findings highlight that CREB activation in epithelial cells under ACP conditions facilitates crosstalk with myeloid cells, promoting IL-1ra upregulation in neutrophils and macrophages. This CREB-driven regulation of IL-1ra in myeloid cells contributes to inflammation-associated tumorigenesis. Targeting this axis may offer a novel therapeutic approach to curb pancreatic cancer progression. Citation Format: Siddharth Mehra, Sudhakar Jinka, Varun Krishnamoorthy, Supriya Srinivasan, Anna Bianchi, Andrew Adams, Haleh Amirian, Manan Patel, Jashodeep Datta, Nipun Merchant, Nagaraj Nagathihalli. Innate immune cell dynamics and pancreatic tumor progression in alcoholic pancreatitis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A051.