Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma

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-be...

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Bibliographic Details
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:	eng
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
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Summary:	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.
ISSN:	1422-0067 1661-6596 1422-0067