Targeting glycolysis in macrophages confers protection against pancreatic ductal adenocarcinoma

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

doi:10.3390/ijms22126350

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Journal article

Targeting glycolysis in macrophages confers protection against pancreatic ductal adenocarcinoma

Penny, Hweixian Leong Singapore Immunology Network, A*STAR, Singapore
Sieow, Je Lin Singapore Immunology Network, A*STAR, Singapore
Gun, Sin Yee Singapore Immunology Network, A*STAR, Singapore
Lau, Mai Chan Singapore Immunology Network, A*STAR, Singapore
Lee, Bernett Singapore Immunology Network, A*STAR, Singapore
Tan, Jasmine Singapore Immunology Network, A*STAR, Singapore
Phua, Cindy Singapore Immunology Network, A*STAR, Singapore
Toh, Florida Singapore Immunology Network, A*STAR, Singapore
Nga, Yvonne Singapore Immunology Network, A*STAR, Singapore
Yeap, Wei Hseun Singapore Immunology Network, A*STAR, Singapore
Janela, Baptiste Skin Research Institute of Singapore (SRIS), Singapore
Kumar, Dilip Singapore Immunology Network, A*STAR, Singapore
Chen, Hao Singapore Immunology Network, A*STAR, Singapore
Yeong, Joe Singapore Immunology Network, A*STAR, Singapore
Kenkel, Justin A. Department of Pathology, Stanford University School of Medicine, Palo Alto CA, USA
Pang, Angela National University Cancer Institute Singapore, NUH Medical Centre (NUHMC), Singapore
Lim, Diana Department of Pathology, National University Health System, National University Hospital, Singapore
Toh, Han Chong National Cancer Centre, Singapore
Hon, Tony Lim Kiat Division of Pathology, Singapore General Hospital, Singapore
Johnson, Christopher I. Perkin Elmer Australia, Melbourne, Australia
Khameneh, Hanif Javanmard Singapore Immunology Network, A*STAR, Singapore - Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Mortellaro, Alessandra Singapore Immunology Network, A*STAR, Singapore
Engleman, Edgar G. Department of Pathology, Stanford University School of Medicine, Palo Alto CA, USA
Rotzschke, Olaf Singapore Immunology Network, A*STAR, Singapore
Ginhoux, Florent Singapore Immunology Network, A*STAR, Singapore
Abastado, Jean-Pierre Singapore Immunology Network, A*STAR, Singapore
Chen, Jinmiao Singapore Immunology Network, A*STAR, Singapore
Wong, Siew Cheng Singapore Immunology Network, A*STAR, Singapore

14.06.2021

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International journal of molecular sciences. - MDPI. - 2021, vol. 22, no. 12, p. 24

Pancreatic ductal adenocarcinoma

English 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.

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