Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis

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 s...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2019-02, Vol.79 (4), p.795-806
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
B7-H1 Antigen - immunology
B7-H1 Antigen - metabolism
Carcinoma, Non-Small-Cell Lung - etiology
Carcinoma, Non-Small-Cell Lung - metabolism
Carcinoma, Non-Small-Cell Lung - pathology
Female
Glycolysis
Humans
Lung Neoplasms - etiology
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Macrophages - immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Nude
Prognosis
T-Lymphocytes - immunology
Tumor Cells, Cultured
Tumor Hypoxia - immunology
Tumor Necrosis Factor-alpha - metabolism
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Summary: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 fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFα to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-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. SIGNIFICANCE: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-18-2545