Adiponectin receptor signaling on dendritic cells blunts antitumor immunity

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...

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Published in:	Cancer research (Chicago, Ill.) Vol. 74; no. 20; pp. 5711 - 5722
Main Authors:	Tan, Peng H, Tyrrell, Helen E J, Gao, Liquan, Xu, Danmei, Quan, Jianchao, Gill, Dipender, Rai, Lena, Ding, Yunchuan, Plant, Gareth, Chen, Yuan, Xue, John Z, Handa, Ashok I, Greenall, Michael J, Walsh, Kenneth, Xue, Shao-An
Format:	Journal Article
Language:	English
Published:	United States 15-10-2014
Subjects:	Adiponectin - physiology Animals Breast Neoplasms - immunology Breast Neoplasms - pathology Cell Line, Tumor Clonal Anergy Cyclooxygenase 2 - metabolism Cytotoxicity, Immunologic Dendritic Cells - metabolism Disease Progression Enzyme Activation Female Humans Interleukin-10 - metabolism MAP Kinase Signaling System Mice, Inbred C57BL Neoplasm Transplantation NF-kappa B - metabolism PPAR gamma - metabolism Receptors, Adiponectin - metabolism T-Lymphocytes, Cytotoxic - immunology Tumor Escape
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.can-13-1397