Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis

Cited 150 time in Web of Science Cited 158 time in Scopus

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; Defrene, 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

Issue Date
American Association for Cancer Research
Cancer Research, Vol.79 No.4, pp.795-806
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.
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Journal Papers (저널논문_의학과)
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Biomedical Sciences (대학원 의과학과)Journal Papers (저널논문_의과학과)
Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Journal Papers (저널논문_수의학과)
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