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

doi:10.3390/ijms22126350

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. JohnsonHanif Javanmard Khameneh, Alessandra Mortellaro, Edgar G. Engleman, Olaf Rotzschke, Florent Ginhoux, Jean Pierre Abastado, Jinmiao Chen, Siew Cheng Wong

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

18 Citations (Scopus)

Résumé

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.

langue originale	Anglais
Numéro d'article	6350
journal	International Journal of Molecular Sciences
Volume	22
Numéro de publication	12
Les DOIs	https://doi.org/10.3390/ijms22126350
état	Publié - 2 juin 2021
Modification externe	Oui

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10.3390/ijms22126350

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Penny, H. L., Sieow, J. L., Gun, S. Y., Lau, M. C., Lee, B., Tan, J., Phua, C., Toh, F., Nga, Y., Yeap, W. H., Janela, B., Kumar, D., Chen, H., Yeong, J., Kenkel, J. A., Pang, A., Lim, D., Toh, H. C., Hon, T. L. K., ... Wong, S. C. (2021). Targeting glycolysis in macrophages confers protection against pancreatic ductal adenocarcinoma. International Journal of Molecular Sciences, 22(12), Article 6350. https://doi.org/10.3390/ijms22126350

@article{0f6aa2305ff049c6b712c0b03a909ba3,

title = "Targeting glycolysis in macrophages confers protection against pancreatic ductal adenocarcinoma",

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 = "Glycolysis, Immunometabolism, Macrophage, Pancreatic ductal adenocarcinoma",

author = "Penny, {Hweixian Leong} and Sieow, {Je Lin} and Gun, {Sin Yee} and Lau, {Mai Chan} and Bernett Lee and Jasmine Tan and Cindy Phua and Florida Toh and Yvonne Nga and Yeap, {Wei Hseun} and Baptiste Janela and Dilip Kumar and Hao Chen and Joe Yeong and Kenkel, {Justin A.} and Angela Pang and Diana Lim and Toh, {Han Chong} and Hon, {Tony Lim Kiat} and Johnson, {Christopher I.} and Khameneh, {Hanif Javanmard} and Alessandra Mortellaro and Engleman, {Edgar G.} and Olaf Rotzschke and Florent Ginhoux and Abastado, {Jean Pierre} and Jinmiao Chen and Wong, {Siew Cheng}",

note = "Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = jun,

day = "2",

doi = "10.3390/ijms22126350",

language = "English",

volume = "22",

journal = "International Journal of Molecular Sciences",

issn = "1661-6596",

number = "12",

}

Penny, HL, Sieow, JL, Gun, SY, Lau, MC, Lee, B, Tan, J, Phua, C, Toh, F, Nga, Y, Yeap, WH, Janela, B, Kumar, D, Chen, H, Yeong, J, Kenkel, JA, Pang, A, Lim, D, Toh, HC, Hon, TLK, Johnson, CI, Khameneh, HJ, Mortellaro, A, Engleman, EG, Rotzschke, O, Ginhoux, F, Abastado, JP, Chen, J & Wong, SC 2021, 'Targeting glycolysis in macrophages confers protection against pancreatic ductal adenocarcinoma', International Journal of Molecular Sciences, VOL. 22, Numéro 12, 6350. https://doi.org/10.3390/ijms22126350

TY - JOUR

T1 - Targeting glycolysis in macrophages confers protection against pancreatic ductal adenocarcinoma

AU - Penny, Hweixian Leong

AU - Sieow, Je Lin

AU - Gun, Sin Yee

AU - Lau, Mai Chan

AU - Lee, Bernett

AU - Tan, Jasmine

AU - Phua, Cindy

AU - Toh, Florida

AU - Nga, Yvonne

AU - Yeap, Wei Hseun

AU - Janela, Baptiste

AU - Kumar, Dilip

AU - Chen, Hao

AU - Yeong, Joe

AU - Kenkel, Justin A.

AU - Pang, Angela

AU - Lim, Diana

AU - Toh, Han Chong

AU - Hon, Tony Lim Kiat

AU - Johnson, Christopher I.

AU - Khameneh, Hanif Javanmard

AU - Mortellaro, Alessandra

AU - Engleman, Edgar G.

AU - Rotzschke, Olaf

AU - Ginhoux, Florent

AU - Abastado, Jean Pierre

AU - Chen, Jinmiao

AU - Wong, Siew Cheng

PY - 2021/6/2

Y1 - 2021/6/2

N2 - 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.

AB - 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.

KW - Glycolysis

KW - Immunometabolism

KW - Macrophage

KW - Pancreatic ductal adenocarcinoma

UR - http://www.scopus.com/inward/record.url?scp=85107759274&partnerID=8YFLogxK

U2 - 10.3390/ijms22126350

DO - 10.3390/ijms22126350

M3 - Article

C2 - 34198548

AN - SCOPUS:85107759274

SN - 1661-6596

VL - 22

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 12

M1 - 6350

ER -