title: Adiponectin receptor signaling on dendritic cells blunts antitumor immunity.
abstract: Immune escape is a fundamental trait of cancer. Dendritic cells (DC) that interact with T cells represent a crucial site for the development of tolerance to tumor antigens, but there remains incomplete knowledge about how DC-tolerizing signals evolve during tumorigenesis. In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. Mechanistic investigations of ligand-receptor interactions on DCs revealed novel signaling pathways for each receptor. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways. Stimulation of these pathways was sufficient to block activation of NF-κB in DC, thereby attenuating their ability to stimulate antigen-specific T-cell responses. Together, our findings reveal novel insights into how DC-tolerizing signals evolve in cancer to promote immune escape. Furthermore, by defining a critical role for adiponectin signaling in this process, our work suggests new and broadly applicable strategies for immunometabolic therapy in patients with cancer.
authors.affiliation: Genetic Engineering Laboratory, College of Biotechnology, Xi'An University, Xian, P.R. China. Nuffield Department of Surgical Sciences, Oxford University, Oxford, United Kingdom. Oxford Breast Unit, Oxford Radcliffe Hospitals NHS Trust, John Radcliffe Hospital, Headley Way, Oxford, United Kingdom. shao-an.xue@ucl.ac.uk peng.tan@nhs.net.
authors.forename: Peng H
authors.initials: PH
authors.lastname: Tan
authors.affiliation: Nuffield Department of Surgical Sciences, Oxford University, Oxford, United Kingdom.
authors.forename: Helen E J
authors.initials: HE
authors.lastname: Tyrrell
authors.affiliation: Department of Immunology, University College London Medical School, Royal Free Hospital, London, United Kingdom.
authors.forename: Liquan
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Haematology, Tongji Medical College, Huazhong University of Science and Technology, Tongji Hospital, Hubei, P.R. China.
authors.forename: Danmei
authors.initials: D
authors.lastname: Xu
authors.affiliation: Nuffield Department of Surgical Sciences, Oxford University, Oxford, United Kingdom.
authors.forename: Jianchao
authors.initials: J
authors.lastname: Quan
authors.affiliation: Nuffield Department of Surgical Sciences, Oxford University, Oxford, United Kingdom.
authors.forename: Dipender
authors.initials: D
authors.lastname: Gill
authors.affiliation: Department of Haematology, University College London Medical School, Royal Free Hospital, London, United Kingdom.
authors.forename: Lena
authors.initials: L
authors.lastname: Rai
authors.affiliation: Division of Internal Medicine, Department of Endocrinology, Tongji Medical College, Huazhong University of Science and Technology, Tongji Hospital, Hubei, P.R. China.
authors.forename: Yunchuan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Nuffield Department of Surgical Sciences, Oxford University, Oxford, United Kingdom.
authors.forename: Gareth
authors.initials: G
authors.lastname: Plant
authors.affiliation: Department of Immunology, University College London Medical School, Royal Free Hospital, London, United Kingdom.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, New York.
authors.forename: John Z
authors.initials: JZ
authors.lastname: Xue
authors.affiliation: Nuffield Department of Surgical Sciences, Oxford University, Oxford, United Kingdom.
authors.forename: Ashok I
authors.initials: AI
authors.lastname: Handa
authors.affiliation: Oxford Breast Unit, Oxford Radcliffe Hospitals NHS Trust, John Radcliffe Hospital, Headley Way, Oxford, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Greenall
authors.affiliation: Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.affiliation: Genetic Engineering Laboratory, College of Biotechnology, Xi'An University, Xian, P.R. China. Department of Immunology, University College London Medical School, Royal Free Hospital, London, United Kingdom. shao-an.xue@ucl.ac.uk peng.tan@nhs.net.
authors.forename: Shao-An
authors.initials: SA
authors.lastname: Xue
mesh_terms: D052242:Adiponectin / Q000502:physiology; D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D017635:Clonal Anergy; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000378:metabolism*; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D047495:PPAR gamma / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019139:Tumor Escape
chemical_list: C475418:ADIPOR1 protein, human; C475420:ADIPOR2 protein, human; D052242:Adiponectin; C508609:IL10 protein, human; D016328:NF-kappa B; D047495:PPAR gamma; D054419:Receptors, Adiponectin; D016753:Interleukin-10; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human