wzb117 and Inflammation

Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1β inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.

Topics: Adenocarcinoma; Animals; Carcinoma, Pancreatic Ductal; Cell Proliferation; Cytoprotection; Drug Resistance, Neoplasm; Glucose Transporter Type 1; Glycolysis; Humans; Hydroxybenzoates; Inflammation; Interleukin-1beta; Killer Cells, Natural; Macrophages; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Pancreatic Neoplasms; Survival Analysis; T-Lymphocytes, Cytotoxic; Tumor Burden