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Cancer Res. 2014 Oct 15;74(20):5711-22. doi: 10.1158/0008-5472.CAN-13-1397. Epub 2014 Sep 26.

Adiponectin receptor signaling on dendritic cells blunts antitumor immunity.

Author information

1
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.
2
Nuffield Department of Surgical Sciences, Oxford University, Oxford, United Kingdom.
3
Department of Immunology, University College London Medical School, Royal Free Hospital, London, United Kingdom.
4
Department of Haematology, Tongji Medical College, Huazhong University of Science and Technology, Tongji Hospital, Hubei, P.R. China.
5
Department of Haematology, University College London Medical School, Royal Free Hospital, London, United Kingdom.
6
Division of Internal Medicine, Department of Endocrinology, Tongji Medical College, Huazhong University of Science and Technology, Tongji Hospital, Hubei, P.R. China.
7
Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, New York.
8
Oxford Breast Unit, Oxford Radcliffe Hospitals NHS Trust, John Radcliffe Hospital, Headley Way, Oxford, United Kingdom.
9
Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.
10
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.

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.

PMID:
25261236
PMCID:
PMC4314963
DOI:
10.1158/0008-5472.CAN-13-1397
[Indexed for MEDLINE]
Free PMC Article

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