title: Lipid mediator lipoxin A4 inhibits tumor growth by targeting IL-10-producing regulatory B (Breg) cells.
abstract: Lipoxin A4 (LXA4), an arachidonic acid-derived anti-inflammatory lipid mediator, shows anti-tumor potential by regulating tumor immune microenvironments. However, the underlying molecular and cellular basis of this function remains unclear. IL-10-producing B (Breg) cells display tumor-promoting effects by negatively regulating anti-tumor immunity. Here we show that LXA4 inhibits tumor growth by suppressing the generation of Breg cells in tumor-bearing mice. The administration of LXA4 inhibited the induction of Breg cells. Breg cell deficiency, in turn, resulted in LXA4 losing its anti-tumor properties. Intriguingly, regulatory T (Treg) cells also had a role in this process. Targeting Breg cells by LXA4 decreased the number of Treg cells in draining lymph nodes and tumor tissues as well as enhanced cytotoxic T cell activities. In addition, we further demonstrated that LXA4 inhibited Breg cells through its dephosphorylating STAT3 and ERK. These findings unveil a new anti-tumor mechanism underlying LXA4 targeting Breg cells with potential clinical applications.
authors.affiliation: Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Tang
authors.affiliation: Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Gynecology and Obstetrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Keke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Shunqun
authors.initials: S
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
authors.forename: Duyun
authors.initials: D
authors.lastname: Ye
authors.affiliation: Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China; State Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China. Electronic address: tjhuangbo@hotmail.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
mesh_terms: D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D044045:Lipoxins / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D044045:Lipoxins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C040527:lipoxin A4; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Breg cells; Inhibition; Lipoxin A4; Tumor