Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 4; pp. 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: Journal Article
• Language: English
• Published: United States 15-02-2019
• 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
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-2545

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.