Card9 Induces Metabolic Reprogramming And Mediates The Immune Cascades In Dendritic Cell Against Pancreatic Cancer Progression

Abstract Caspase recruitment domain family member 9 (CARD9), a signaling adaptor protein, transduces the immune signals from pattern recognition receptors (PRR) and induces the cascaded immune response, which plays a critical role in innate and adaptive immunity. In order to explore the role of CARD9 in DCs during pancreatic cancer (PC) progression and its underlying mechanism, samples of PC in patients with different clinical stages, animal model of PC, simulated immune microenvironment in vitro were employed. We found that the immunogenicity of bone marrow-derived DCs decreased in the progression of PC, which was accompanied with downregulated CARD9 expression. And the glycolysis in DCs was attenuated accompanied with diminishing glucose uptake and reducing acidic metabolites production after CARD9 knockdown, while fatty acid oxidation (FAO) was lifted. Further, CARD9 deficiency weakened the DCs migration, antigen presentation and stimulation to CD8+ T cell immune response. Mechanically, activated CARD9 recruited Bcl10 and MALT1 and constructed CARD9-Bcl10-MALT1 signalosomes, followed by the PI3K/AKT/mTOR pathway mediated metabolic switching and NF-κB pathway induced inflammatory cascades. Furthermore, DCs with CARD9 overexpression loading antigenic peptide mucin 1 (MUC1) curbed tumor growth in mice with PC subcutaneously implanted tumor. These results reveal a new role of CARD9 as a molecular switch of glycolysis in DCs that triggers the metabolic reprogramming, antigen presentation and antitumor effects of CD8+ T cells.