International Journal of Molecular Sciences (Jun 2021)
Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma
- 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
Affiliations
- Hweixian Leong Penny
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Je Lin Sieow
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Sin Yee Gun
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Mai Chan Lau
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Bernett Lee
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Jasmine Tan
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Cindy Phua
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Florida Toh
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Yvonne Nga
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Wei Hseun Yeap
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Baptiste Janela
- Skin Research Institute of Singapore (SRIS), 11 Mandalay Road, #17-01 Clinical Sciences Building, Singapore 308232, Singapore
- Dilip Kumar
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Hao Chen
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Joe Yeong
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Justin A. Kenkel
- Department of Pathology, Stanford University School of Medicine, 3373 Hillview Ave., Palo Alto, CA 94304, USA
- Angela Pang
- National University Cancer Institute Singapore, NUH Medical Centre (NUHMC) @ Levels 8-10, 5 Lower Kent Ridge Road, Singapore 119074, Singapore
- Diana Lim
- Department of Pathology, National University Health System, National University Hospital, Lower Kent Ridge Road, 1 Main Building, Level 3, Singapore 119074, Singapore
- Han Chong Toh
- National Cancer Centre, 11 Hospital Crescent, Singapore 169610, Singapore
- Tony Lim Kiat Hon
- Division of Pathology, Singapore General Hospital, 20 College Road, Academia, Level 7, Singapore 169856, Singapore
- Christopher I. Johnson
- Perkin Elmer Australia, 530-540 Springvale Road, Melbourne VIC 3150, Australia
- Hanif Javanmard Khameneh
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Alessandra Mortellaro
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Edgar G. Engleman
- Department of Pathology, Stanford University School of Medicine, 3373 Hillview Ave., Palo Alto, CA 94304, USA
- Olaf Rotzschke
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Florent Ginhoux
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Jean-Pierre Abastado
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Jinmiao Chen
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- Siew Cheng Wong
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore
- DOI
- https://doi.org/10.3390/ijms22126350
- Journal volume & issue
-
Vol. 22,
no. 12
p. 6350
Abstract
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.
Keywords
