Format

Send to

Choose Destination
J Clin Invest. 2019 Feb 1;129(2):631-646. doi: 10.1172/JCI123027. Epub 2019 Jan 7.

Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α-mediated tumor progression.

Author information

1
Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
2
Institute of Pathology, Tongji Hospital, HUST, Wuhan, China.
3
Department of Pathology, School of Basic Medicine, and.
4
The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, HUST, Wuhan, China.
5
Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.
6
Department of Surgery, Tongji Hospital, HUST, Wuhan, China.
7
Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, HUST, Wuhan, China.
8
Department of Otolaryngology, Head and Neck Surgery, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, China.
9
Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom.

Abstract

Macrophages perform key functions in tissue homeostasis that are influenced by the local tissue environment. Within the tumor microenvironment, tumor-associated macrophages can be altered to acquire properties that enhance tumor growth. Here, we found that lactate, a metabolite found in high concentration within the anaerobic tumor environment, activated mTORC1 that subsequently suppressed TFEB-mediated expression of the macrophage-specific vacuolar ATPase subunit ATP6V0d2. Atp6v0d2-/- mice were more susceptible to tumor growth, with enhanced HIF-2α-mediated VEGF production in macrophages that display a more protumoral phenotype. We found that ATP6V0d2 targeted HIF-2α but not HIF-1α for lysosome-mediated degradation. Blockade of HIF-2α transcriptional activity reversed the susceptibility of Atp6v0d2-/- mice to tumor development. Furthermore, in a cohort of patients with lung adenocarcinoma, expression of ATP6V0d2 and HIF-2α was positively and negatively correlated with survival, respectively, suggesting a critical role of the macrophage lactate/ATP6V0d2/HIF-2α axis in maintaining tumor growth in human patients. Together, our results highlight the ability of tumor cells to modify the function of tumor-infiltrating macrophages to optimize the microenvironment for tumor growth.

KEYWORDS:

Immunology; Lysosomes; Macrophages; Oncology

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center