Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis
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SCOPUS
- Title
- Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis
- Authors
- AHN, G ONE; 정회빈; 김세희; 홍범주; 이찬주; 김영은; 복서연; 오정민; 곽승희; 유민영; 이민선; 정석진; Defrene J; Tessier P; Pelletier M; 전형린; 노태영; 김범주; KIM, KI HEAN; 주지현; 김성지; 이윤진; 김동완; 김일한; 김학재; 박종완; 이윤상; 이재성; 천기정; Irving Weissman; 정두현; 전윤경
- Date Issued
- 2019-02-15
- Publisher
- AMER ASSOC CANCER RESEARCH
- 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 TNF alpha 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.
- Keywords
- ACTIVATED PROTEIN-KINASE; T-CELL FUNCTION; INDUCIBLE FACTOR-1-ALPHA; CANCER-CELLS; EXPRESSION; ANGIOGENESIS; RECEPTOR; METABOLISM; MONOCYTES; BLOCKADE
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/94901
- DOI
- 10.1158/0008-5472.CAN-18-2545
- ISSN
- 0008-5472
- Article Type
- Article
- Citation
- CANCER RESEARCH, vol. 79, no. 4, page. 795 - 806, 2019-02-15
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