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 language | English |
|---|---|
| Pages (from-to) | 795-806 |
| Number of pages | 12 |
| Journal | Cancer Research |
| Volume | 79 |
| Issue number | 4 |
| DOIs | |
| State | Published - 15 Feb 2019 |
Bibliographical note
Funding Information:We would like to thank Dr. J. Martin Brown (Stanford University) for LLC cell line and 5 HRE-GFP construct, Drs. Mark Dewhirst and Gregory Palmer (Duke University) for sharing in vivo dorsal window chamber techniques, and Drs. Andrew Minchinton and Kevin Bennewith (British Columbia Cancer Research Centre) for in vivo Hoechst 33342 FACS protocol. We are grateful to Kook-Chan Heo at GENIA Inc. and Sang-Kwon Lee at Hana BioTech for arranging animal housing and transportation between POSTECH and Seoul National University College of Medicine. Geun Bae Ko and Kyeong Yun Kim at the Department of Nuclear Medicine, Seoul National University College of Medicine, are also acknowledged for their contributions for developing the small animal PET/MRI instrument used in this study. We also appreciate help from Narae Park (Seoul St. Mary's Hospital) for reagents, Ji Yong Park (the Department of Nuclear Medicine, Seoul National University College of Medicine) with ferumoxytol preparation and technical information, A-Ram Kim (KIRAM) for a mouse lung cancer model, and Hyung-Seok Choi (POSTECH) for sharing a protocol analyzing T cells in tumors. Special thanks go to the staffs at the FACS core and animal facility at POSTECH for their technical and maintenance support; staffs at the Department of Pathology at Seoul National University College of Medicine for handling and preparing patients' specimen. This work was supported by grants from the National R&D Program for Cancer Control, the Ministry of Health and Welfare (1320220 to G.-O. Ahn); the Ministry of Science, ICT, and Future Planning Korea (grant numbers NRF-2017M2A2A7A01015968 and NRF-2018R1A2B6004453 to G.-O. Ahn; NRF-2017M2A2A7A01070925 to H.J. Kim); 4th Green Science grant from Pohang Steel Company (POSCO) to G.-O. Ahn; Ludwig Cancer Foundation to I.L. Weissman; and BK21 Plus program from the Ministry of Education Korea (Grant No. 10Z20130012243). B.-J. Hong (NRF-2013H1A2A1032808) and Y.-E. Kim (NRF-2012H1A2A1002871) are Global PhD fellows supported by the Ministry of Science, ICT, and Future Planning Korea; H. Jeong is a recipient of TJ Park CheongAm POSCO Science Fellowship.
Funding Information:
We would like to thank Dr. J. Martin Brown (Stanford University) for LLC cell line and 5 ⨯ HRE-GFP construct, Drs. Mark Dewhirst and Gregory Palmer (Duke University) for sharing in vivo dorsal window chamber techniques, and Drs. Andrew Minchinton and Kevin Bennewith (British Columbia Cancer Research Centre) for in vivo Hoechst 33342 FACS protocol. We are grateful to Kook-Chan Heo at GENIA Inc. and Sang-Kwon Lee at Hana BioTech for arranging animal housing and transportation between POSTECH and Seoul National University College of Medicine. Geun Bae Ko and Kyeong Yun Kim at the Department of Nuclear Medicine, Seoul National University College of Medicine, are also acknowledged for their contributions for developing the small animal PET/MRI instrument used in this study. We also appreciate help from Narae Park (Seoul St. Mary's Hospital) for reagents, Ji Yong Park (the Department of Nuclear Medicine, Seoul National University College of Medicine) with ferumoxytol preparation and technical information, A-Ram Kim (KIRAM) for a mouse lung cancer model, and Hyung-Seok Choi (POSTECH) for sharing a protocol analyzing T cells in tumors. Special thanks go to the staffs at the FACS core and animal facility at POSTECH for their technical and maintenance support; staffs at the Department of Pathology at Seoul National University College of Medicine for handling and preparing patients' specimen. This work was supported by grants from the National R&D Program for Cancer Control, the Ministry of Health and Welfare (1320220 to G.-O. Ahn); the Ministry of Science, ICT, and Future Planning Korea (grant numbers NRF-2017M2A2A7A01015968 and NRF-2018R1A2B6004453 to G.-O. Ahn; NRF-2017M2A2A7A01070925 to H.J. Kim); 4th Green Science grant from Pohang Steel Company (POSCO) to G.-O. Ahn; Ludwig Cancer Foundation to I.L. Weissman; and BK21 Plus program from the Ministry of Education Korea (Grant No. 10Z20130012243). B.-J. Hong (NRF-2013H1A2A1032808) and Y.-E. Kim (NRF-2012H1A2A1002871) are GlobalPhDfellowssupportedbytheMinistryofScience,ICT,andFuturePlanning Korea; H. Jeong is a recipient of TJ Park CheongAm POSCO Science Fellowship.
Publisher Copyright:
© 2019 American Association for Cancer Research.
