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Cancer Res. 2019 Feb 15;79(4):795-806. doi: 10.1158/0008-5472.CAN-18-2545. Epub 2019 Jan 4.

Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis.

Author information

1
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea.
2
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
3
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.
4
Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, Ville de Québec, Québec, Canada.
5
Department of Life Sciences, POSTECH, Pohang, Gyeongbuk, Korea.
6
Department of Mechanical Engineering, POSTECH, Pohang, Gyeongbuk, Korea.
7
Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, Korea.
8
Department of Chemistry, POSTECH, Pohang, Gyeongbuk, Korea.
9
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
10
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
11
Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.
12
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
13
Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Korea.
14
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
15
Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California.
16
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea. goneahn@gmail.com ykjeon@snu.ac.kr.
17
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Korea. goneahn@gmail.com ykjeon@snu.ac.kr.
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Contributed equally

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 18fluoro-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 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.

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