Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α–mediated tumor progression
Na Liu, … , Guoping Wang, Xiang-Ping Yang
Na Liu, … , Guoping Wang, Xiang-Ping Yang
Published February 1, 2019; First published November 15, 2018
Citation Information: J Clin Invest. 2019;129(2):631-646. https://doi.org/10.1172/JCI123027.
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Research Article Immunology Oncology

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

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.

Authors

Na Liu, Jing Luo, Dong Kuang, Sanpeng Xu, Yaqi Duan, Yu Xia, Zhengping Wei, Xiuxiu Xie, Bingjiao Yin, Fang Chen, Shunqun Luo, Huicheng Liu, Jing Wang, Kan Jiang, Feili Gong, Zhao-hui Tang, Xiang Cheng, Huabin Li, Zhuoya Li, Arian Laurence, Guoping Wang, Xiang-Ping Yang

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Figure 4

Deletion of Atp6v0d2 leads to enhanced protumoral polarization of macrophages.

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Deletion of Atp6v0d2 leads to enhanced protumoral polarization of macrop...
(A–D) WT and Atp6v0d2–/– mice were injected s.c. with 5 × 105 LLC cells. On day 15 after inoculation, mice were sacrificed. (A and B) Representative flow cytometric plots of tumor-infiltrating, gated F4/80+cells showing CD11C+CD206– (proinflammatory) and CD11C–CD206+ (protumoral) TAM fractions in LLC tumor xenograft model (A) and comparisons of fractions of CD11C+CD206– and CD11C–CD206+ in TAMs between WT and Atp6v0d2–/– mice (B) (n = 5). (C) The expression of Mrc1, Arg1, Fizz1, Il1b, and Il6 in WT and Atp6v0d2–/– (KO) tumor tissues was determined by qRT-PCR (n = 5). (D) TAMs from tumor-bearing WT and Atp6v0d2–/– mice were isolated with CD11b magnetic beads. The expression of Mrc1, Arg1, Fizz1, Il1b, and Il6 was determined by qRT-PCR (n = 5). (E and F) WT and Atp6v0d2–/– BMDMs were stimulated with medium or LLC TCM for 36 hours. The expression of Arg1 (E) and Fizz1 (F) was determined by qRT-PCR. (G and H) WT and Atp6v0d2–/– BMDMs were stimulated with medium or LLC TCM for 6 hours. The expression of Il1b (G) and Il6 (H) was determined by qRT-PCR. Data are representative of 2 (A–D) or 3 (E–H) independent experiments. Data were assessed by unpaired Student’s t test and are represented as mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001. NS, not significant.