Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma

• Published in: International journal of molecular sciences 2021-06, Vol.22 (12), p.6350
• Main Authors: Penny, Hweixian Leong, Sieow, Je Lin, Gun, Sin Yee, Lau, Mai Chan, Lee, Bernett, Tan, Jasmine, Phua, Cindy, Toh, Florida, Nga, Yvonne, Yeap, Wei Hseun, Janela, Baptiste, Kumar, Dilip, Chen, Hao, Yeong, Joe, Kenkel, Justin A, Pang, Angela, Lim, Diana, Toh, Han Chong, Hon, Tony Lim Kiat, Johnson, Christopher I, Khameneh, Hanif Javanmard, Mortellaro, Alessandra, Engleman, Edgar G, Rotzschke, Olaf, Ginhoux, Florent, Abastado, Jean-Pierre, Chen, Jinmiao, Wong, Siew Cheng
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - immunology; Adenocarcinoma - pathology; Animals; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - pathology; CD8 antigen; Cell Proliferation - drug effects; Cytoprotection - drug effects; Cytotoxicity; Dehydrogenases; Drug Resistance, Neoplasm - drug effects; Enzymes; Gemcitabine; Glucose; Glucose transporter; Glucose Transporter Type 1 - metabolism; Glycolysis; Glycolysis - drug effects; Humans; Hydroxybenzoates - pharmacology; Hypoxia; immunometabolism; Inflammasomes; Inflammation; Inflammation - pathology; Interleukin 1; Interleukin-1beta - metabolism; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Lymphocytes; Lymphocytes T; macrophage; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Metabolism; Mice; Mice, Inbred C57BL; Natural killer cells; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Pancreas; Pancreatic cancer; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Survival Analysis; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Tumor Burden - drug effects; Tumor microenvironment; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22126350

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.