Abstract B088: Targeting bile acids mitigates PDAC Tumor Burden and induces anti-tumor immunity

Abstract

It is well appreciated that dietary metabolites can influence health outcomes. However, the various mechanisms by which some dietary metabolites influence health and treatment responses remain unknown. One metabolite subgroup that warrants further investigation is bile acids, which are derived from cholesterol in the liver and can be converted into secondary bile acids by the gut microbiome. They are dysregulated in many diseases such as cancer and are upregulated in pancreatic adenocarcinoma (PDAC) patients. Pancreatic cancer has an average five-year survival rate of 13%, and patients do not respond well to conventional chemotherapy and immunotherapy, highlighting the need for novel therapeutic strategies. In addition to metabolites, our lab is broadly focused on the immune microenvironment with a concentration on macrophages. Macrophages make up a significant portion of the immune cells in PDAC patient tumors and are often immunosuppressive. We performed spatial transcriptomics on tumor tissue from mice with PDAC, focusing on macrophage-high regions of the tumors, and found increased bile acid metabolism gene pathways in treatment-resistant compared to treatment-responsive tumors. This suggested that bile acid signaling could impact macrophages to make a more immunosuppressive tumor microenvironment that is less responsive to treatment. One way to target bile acid signaling in PDAC is through z-guggulsterone (zGS), a plant-derived FXR (bile acid receptor) antagonist. This drug has been shown to induce apoptosis in pancreatic cancer cell lines, but research on its impact on the immune microenvironment in PDAC is lacking. Therefore, we treated mice with PDAC with zGS and chemotherapy and found the combination strategy to be the most effective at tumor growth reduction, and that zGS boosts immune activation. We also observed larger orthotopic PDAC tumors in mice on a high cholesterol diet (HCD) and significant increases in secreted fecal bile acids, particularly lithocholic acid (LCA) derivatives. Treating mice with LCA decreased tumor growth and increased immune activation in cells, including macrophages. To study the impacts of LCA on macrophages specifically, we isolated bone-marrow-derived macrophages (BMDMs) from mice and cultured them in the presence or absence of LCA and tumor cell-derived supernatant (TCS) to mimic the tumor microenvironment. We collected RNA from these macrophages and found that LCA reduced immunosuppressive mRNAs by real-time quantitative PCR. RNA sequencing of these samples displayed increases in interferon pathway genes indicating that LCA may exert its anti-tumor effects through interferons in macrophages. Overall, we have found that targeting specific bile acids and their signaling can decrease tumor growth, showing potential as novel treatment modalities for PDAC and other cancers.