Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma
| Autor: | Hweixian Leong Penny, Je Lin Sieow, Sin Yee Gun, Mai Chan Lau, Bernett Lee, Jasmine Tan, Cindy Phua, Florida Toh, Yvonne Nga, Wei Hseun Yeap, Baptiste Janela, Dilip Kumar, Hao Chen, Joe Yeong, Justin A. Kenkel, Angela Pang, Diana Lim, Han Chong Toh, Tony Lim Kiat Hon, Christopher I. Johnson, Hanif Javanmard Khameneh, Alessandra Mortellaro, Edgar G. Engleman, Olaf Rotzschke, Florent Ginhoux, Jean-Pierre Abastado, Jinmiao Chen, Siew Cheng Wong |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 12, p 6350 (2021) |
| Druh dokumentu: | article |
| ISSN: | 1422-0067 1661-6596 |
| DOI: | 10.3390/ijms22126350 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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