Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis

Hoibin Jeong, Sehui Kim, Beom Ju Hong, Chan Ju Lee, Young Eun Kim, Seoyeon Bok, Jung Min Oh, Seung Hee Gwak, Min Young Yoo, Min Sun Lee, Seock Jin Chung, Joan Defrêne, Philippe Tessier, Martin Pelletier, Hyeongrin Jeon, Tae Young Roh, Bumju Kim, Ki Hean Kim, Ji Hyeon Ju, Sungjee KimYoon Jin Lee, Dong Wan Kim, Il Han Kim, Hak Jae Kim, Jong Wan Park, Yun Sang Lee, Jae Sung Lee, Gi Jeong Cheon, Irving L. Weissman, Doo Hyun Chung, Yoon Kyung Jeon, G. One Ahn

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non–small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18 fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFa to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome prolif-erator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy.

Original languageEnglish
Pages (from-to)795-806
Number of pages12
JournalCancer Research
Volume79
Issue number4
DOIs
StatePublished - 15 Feb 2019

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Glycolysis
Macrophages
Neoplasms
Non-Small Cell Lung Carcinoma
Tumor Hypoxia
Clodronic Acid
Ligands
AMP-Activated Protein Kinases
Peroxisomes
R Factors
Atlases
Deoxyglucose
Immunotherapy

Cite this

Jeong, H., Kim, S., Hong, B. J., Lee, C. J., Kim, Y. E., Bok, S., ... Ahn, G. O. (2019). Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis. Cancer Research, 79(4), 795-806. https://doi.org/10.1158/0008-5472.CAN-18-2545
Jeong, Hoibin ; Kim, Sehui ; Hong, Beom Ju ; Lee, Chan Ju ; Kim, Young Eun ; Bok, Seoyeon ; Oh, Jung Min ; Gwak, Seung Hee ; Yoo, Min Young ; Lee, Min Sun ; Chung, Seock Jin ; Defrêne, Joan ; Tessier, Philippe ; Pelletier, Martin ; Jeon, Hyeongrin ; Roh, Tae Young ; Kim, Bumju ; Kim, Ki Hean ; Ju, Ji Hyeon ; Kim, Sungjee ; Lee, Yoon Jin ; Kim, Dong Wan ; Kim, Il Han ; Kim, Hak Jae ; Park, Jong Wan ; Lee, Yun Sang ; Lee, Jae Sung ; Cheon, Gi Jeong ; Weissman, Irving L. ; Chung, Doo Hyun ; Jeon, Yoon Kyung ; Ahn, G. One. / Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis. In: Cancer Research. 2019 ; Vol. 79, No. 4. pp. 795-806.
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abstract = "Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non–small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18 fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFa to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome prolif-erator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy.",
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Jeong, H, Kim, S, Hong, BJ, Lee, CJ, Kim, YE, Bok, S, Oh, JM, Gwak, SH, Yoo, MY, Lee, MS, Chung, SJ, Defrêne, J, Tessier, P, Pelletier, M, Jeon, H, Roh, TY, Kim, B, Kim, KH, Ju, JH, Kim, S, Lee, YJ, Kim, DW, Kim, IH, Kim, HJ, Park, JW, Lee, YS, Lee, JS, Cheon, GJ, Weissman, IL, Chung, DH, Jeon, YK & Ahn, GO 2019, 'Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis', Cancer Research, vol. 79, no. 4, pp. 795-806. https://doi.org/10.1158/0008-5472.CAN-18-2545

Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis. / Jeong, Hoibin; Kim, Sehui; Hong, Beom Ju; Lee, Chan Ju; Kim, Young Eun; Bok, Seoyeon; Oh, Jung Min; Gwak, Seung Hee; Yoo, Min Young; Lee, Min Sun; Chung, Seock Jin; Defrêne, Joan; Tessier, Philippe; Pelletier, Martin; Jeon, Hyeongrin; Roh, Tae Young; Kim, Bumju; Kim, Ki Hean; Ju, Ji Hyeon; Kim, Sungjee; Lee, Yoon Jin; Kim, Dong Wan; Kim, Il Han; Kim, Hak Jae; Park, Jong Wan; Lee, Yun Sang; Lee, Jae Sung; Cheon, Gi Jeong; Weissman, Irving L.; Chung, Doo Hyun; Jeon, Yoon Kyung; Ahn, G. One.

In: Cancer Research, Vol. 79, No. 4, 15.02.2019, p. 795-806.

Research output: Contribution to journalArticle

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T1 - Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis

AU - Jeong, Hoibin

AU - Kim, Sehui

AU - Hong, Beom Ju

AU - Lee, Chan Ju

AU - Kim, Young Eun

AU - Bok, Seoyeon

AU - Oh, Jung Min

AU - Gwak, Seung Hee

AU - Yoo, Min Young

AU - Lee, Min Sun

AU - Chung, Seock Jin

AU - Defrêne, Joan

AU - Tessier, Philippe

AU - Pelletier, Martin

AU - Jeon, Hyeongrin

AU - Roh, Tae Young

AU - Kim, Bumju

AU - Kim, Ki Hean

AU - Ju, Ji Hyeon

AU - Kim, Sungjee

AU - Lee, Yoon Jin

AU - Kim, Dong Wan

AU - Kim, Il Han

AU - Kim, Hak Jae

AU - Park, Jong Wan

AU - Lee, Yun Sang

AU - Lee, Jae Sung

AU - Cheon, Gi Jeong

AU - Weissman, Irving L.

AU - Chung, Doo Hyun

AU - Jeon, Yoon Kyung

AU - Ahn, G. One

PY - 2019/2/15

Y1 - 2019/2/15

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