Wei Xiang 1 , Rongchen Shi 1 , Xia Kang 1 , Xuan Zhang 2 , Peng Chen 3 , Lili Zhang 1 , Along Hou 1 , Rui Wang 1 , Yuanyin Zhao 1 , Kun Zhao 1 , Yingzhe Liu 1 , Yue Ma 1 , Huan Luo 1 , Shenglan Shang 1 , Jinyu Zhang 4 , Fengtian He 1 , Songtao Yu 2 , Lixia Gan 1 , Chunmeng Shi 5 , Yongsheng Li , 6 , Wei Yang , 7 , Houjie Liang , 2 , Hongming Miao , 1
3 July 2018
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.
Tumour associated macrophages (TAMs) have an altered lipid metabolism. Here the authors show that downregulation of monoacylglycerols lipase MGLL in TAMs induces lipid accumulation and tumor progression by polarizing TAMs toward tumor-promoting through activation of cannabinoid receptor CB2.