Monoacylglycerol lipase regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression

Wei Xiang, Rongchen Shi, Xia Kang, Xuan Zhang, Peng Chen, Lili Zhang, Along Hou, Rui Wang, Yuanyin Zhao, Kun Zhao, Yingzhe Liu, Yue Ma, Huan Luo, Shenglan Shang, Jinyu Zhang, Fengtian He, Songtao Yu, Lixia Gan, Chunmeng Shi, Yongsheng Li (), Wei Yang (), Houjie Liang () and Hongming Miao ()
Additional contact information
Wei Xiang: Third Military Medical University
Rongchen Shi: Third Military Medical University
Xia Kang: Third Military Medical University
Xuan Zhang: Third Military Medical University
Peng Chen: PLA 324 Hospital
Lili Zhang: Third Military Medical University
Along Hou: Third Military Medical University
Rui Wang: Third Military Medical University
Yuanyin Zhao: Third Military Medical University
Kun Zhao: Third Military Medical University
Yingzhe Liu: Third Military Medical University
Yue Ma: Third Military Medical University
Huan Luo: Third Military Medical University
Shenglan Shang: Third Military Medical University
Jinyu Zhang: Third Military Medical University
Fengtian He: Third Military Medical University
Songtao Yu: Third Military Medical University
Lixia Gan: Third Military Medical University
Chunmeng Shi: Third Military Medical University
Yongsheng Li: Third Military Medical University
Wei Yang: Southern Medical University
Houjie Liang: Third Military Medical University
Hongming Miao: Third Military Medical University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Metabolic reprogramming greatly contributes to the regulation of macrophage activation. However, the mechanism of lipid accumulation and the corresponding function in tumor-associated macrophages (TAMs) remain unclear. With primary investigation in colon cancer and confirmation in other cancer models, here we determine that deficiency of monoacylglycerol lipase (MGLL) results in lipid overload in TAMs. Functionally, macrophage MGLL inhibits CB2 cannabinoid receptor-dependent tumor progression in inoculated and genetic cancer models. Mechanistically, MGLL deficiency promotes CB2/TLR4-dependent macrophage activation, which further suppresses the function of tumor-associated CD8+ T cells. Treatment with CB2 antagonists delays tumor progression in inoculated and genetic cancer models. Finally, we verify that expression of macrophage MGLL is decreased in cancer tissues and positively correlated with the survival of cancer patients. Taken together, our findings identify MGLL as a switch for CB2/TLR4-dependent macrophage activation and provide potential targets for cancer therapy.

Date: 2018
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DOI: 10.1038/s41467-018-04999-8

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