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

Atp6v0d2–/– mice are more susceptible to tumorigenesis.

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Atp6v0d2–/– mice are more susceptible to tumorigenesis. (A–C) Compariso...
(A–C) Comparison of LLC tumor growth in WT and Atp6v0d2–/– mice (n = 7) after implantation: tumor growth rate (A), tumor weight (B), and representative images of excised tumors (C). (D–F) Tumor growth of B16-F10 in WT and Atp6v0d2–/– mice (n = 5) after implantation: tumor growth rate (D), tumor weight (E), and representative images of excised tumors (F). (G) Immunoblot analysis of ATP6V0d2 expression in macrophages, CD4+ T cells, CD8+ T cells, fibroblasts, TAMs, B16-F1, B16-F10, and LLC cells. (H–K) Atp6v0d2–/– mice were challenged s.c. with 5 × 105 LLC cells alone, or together with 2 × 105 either WT BMDMs or Atp6v0d2–/– BMDMs (n = 5). Tumor size was measured every 2 to 3 days (H). Tumor mass was determined at day 15 after inoculation (I). Representative images of tumors are presented (J). All experiments except H–J were repeated 2 times. Data were assessed by unpaired Student’s t test (A, B, D, and E) or 1-way ANOVA with Turkey’s post hoc test (H and I) and are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. NS, not significant. Scale bars: 5 mm (C, F, and J).