Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis

Hoibin Jeong, Sehui Kim, Beom Ju Hong, Chan Ju Lee, Young Eun Kim, Seoyeon Bok, Jung Min Oh, Seung Hee Gwak, Min Young Yoo, Min Sun Lee, Seock Jin Chung, Joan Defrêne, Philippe Tessier, Martin Pelletier, Hyeongrin Jeon, Tae Young Roh, Bumju Kim, Ki Hean Kim, Ji Hyeon Ju, Sungjee KimYoon Jin Lee, Dong Wan Kim, Il Han Kim, Hak Jae Kim, Jong Wan Park, Yun Sang Lee, Jae Sung Lee, Gi Jeong Cheon, Irving L. Weissman, Doo Hyun Chung, Yoon Kyung Jeon, G. One Ahn

Research output: Contribution to journalArticlepeer-review

189 Scopus citations

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 18 fluoro-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 TNFa to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome prolif-erator-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.

Original languageEnglish
Pages (from-to)795-806
Number of pages12
JournalCancer Research
Volume79
Issue number4
DOIs
StatePublished - 15 Feb 2019

Bibliographical note

Publisher Copyright:
© 2019 American Association for Cancer Research.

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