Abstract PO-054: A stromal PTEN/STAT3 signaling axis promotes immune evasion and tumor progression in pancreatic cancer

Pancreatic adenocarcinoma (PDAC) is among the most lethal cancer types, with more than 90% of patients succumbing to the disease within five years of diagnosis. The most notable hallmark of PDAC tumors is an inordinately dense stromal reaction comprised of extracellular matrix proteins, immune infiltrates, endothelial cells, and activated fibroblasts. The stroma experiences a dramatic expansion in parallel with the progression of the tumor, suggesting it is an active participant in PDAC development. However, key studies targeting stromal development through Hedgehog signaling revealed tumor-suppressive functions of the stroma, further complicating the strategy to target the stroma as a single component. Thus, our understanding of the complex relationship between the tumor and its microenvironment and how to effectively target the stroma itself remains incomplete. Previous work by our lab demonstrates that phosphatase and tensin homolog (PTEN) expression is lost in approximately 25% of patients in a PDAC cohort, and lower PTEN expression correlates with worsened patient outcome. Additionally, inhibition of Hedgehog signaling results in loss of PTEN expression and subsequent activation of Akt signaling pathways, and increased tumor growth. The purpose of the current study is to determine the effect of PTEN loss in PDAC cancer-associated fibroblasts (CAFs) on tumor progression and dissemination, and immune evasion. Using a combination of in vitro and in vivo experiments, we have found robust activation of Signal Transducer and Activator of Transcription 3 (STAT3) in PTEN-null pancreatic fibroblasts. We also see selective alterations in the secretome of pancreatic fibroblasts, including a marked increase in IL-6, CXCL1, and CXCL2. Our group has developed a genetically engineered mouse model of PDAC using a dual recombinase system in which the fibroblast-specific protein-1 (FspCre) transgene is used to conditionally delete genes of interest in the fibroblasts of Pdx1Flpki/+;FSF-KrasG12D/+;p53frt/+ (KPF) mice while driving tumorigenesis in the pancreatic epithelium. Conditional deletion of STAT3 in stromal fibroblasts of these mice results in increased overall survival, reduced tumor progression, and alterations within the immune landscape of the tumor microenvironment. Based on our current findings, we believe that a PTEN/STAT3/CXCL1/2 signaling axis within stromal CAFs produces an immunosuppressive tumor microenvironment that favors PDAC progression. Future experiments are needed to validate and confirm this conclusion, including defining the exact mechanisms by which PTEN loss leads to STAT3 activation and elevated secretion of CXCL1/2. This project further highlights the nuanced and complex relationship between PDAC tumor and stroma, and may serve to advance our understanding of how the stroma can be more precisely and effectively targeted to reduce tumor burden and increase the efficacy of immune therapy. Citation Format: Catherine B. MarElia-Bennett, Julia E. Lefler, Michael C. Ostrowski. A stromal PTEN/STAT3 signaling axis promotes immune evasion and tumor progression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-054.