Microenvironment and Immunology 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 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 PPARg pathways. Stimulation of these pathways was sufficient to block activation of NF-kB in DC, thereby attenuating their ability to stimulate antigen-specific T-cell responses. Together, ourfindings 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. Cancer Res; 74(20); 1–12. 2014 AACR. Introduction It is increasingly recognized that adipocytes secrete molecules, termed as adipokines with wide-ranging metabolic effects (1, 2). Leptin has been shown to promote T-cell immunity (3) and inhibit regulatory T-cell proliferation (4). Contrastingly, adiponectin (APN) has been shown to inhibit macrophage function (5, 6), but its far-reaching effects on the adaptive immune system, in particular in the context of cancer immunology are yet to be elucidated. APN can mediate antidiabetic (7, 8), anti-inflammatory (6), and antiatherosclerotic (9, 10) processes. In our study, dendritic cells (DC) isolated from patients with breast cancer with metastatic or locally advanced disease express higher level of APN receptors.Challengingofpatients'DCswith tumor-specificT-cell receptor (TCR) engineered autologous T cells abrogated their antitumoractivity.BlockadeofAdipoR1/R2signalingonDCscan improve antitumor immunity of the tumor-specific T cells. We have therefore sought to explain how APN regulates the DC function, hencemodulating T-cell immunity against cancer. We show here that AdipoR1 signaling in DCs mediates T-cell anergy via IL10-dependent mechanism through activation of theAMPKandMAPKp38 pathways. IL10 promotes further antiinflammatory action via the IL10 receptor in a process that is dependent on the STAT3 and SOCS3 pathways. On the other hand, AdipoR2 activation induces T-cell anergy through a distinctmechanism that utilizes PPARg . The anti-inflammatory actions of PPARg are mediated through inhibition of intracellular free radicals in the DC and promotion of Th2-skewed cytokine production by the subsequent T-cell responses. All thesemechanisms center on regulating the downstreamNF-kB pathway, which in turn arrests DC maturation processes. To test our hypothesis that APN receptor signaling on DCs can inhibit antitumor immunity in vivo, wewent to overexpress either AdipoR1 or AdipoR2 on murine DCs and carried out vaccination study. We show here that AdipoR1/R2 signaling in DCs can interfere with the ability of T-cell clearance of cancer cells in a T-cell–mediated tumor protection model. 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 HospitalsNHSTrust, JohnRadcliffeHospital, HeadleyWay,Oxford,United Kingdom. Department of Immunology,UniversityCollege LondonMedical School, Royal Free Hospital, London, United Kingdom. Department of Haematology, TongjiMedical College,HuazhongUniversity of Science and Technology, Tongji Hospital, Hubei, P.R. China. Department of Haematology, University College London Medical School, Royal Free Hospital, London, United Kingdom. Division of Internal Medicine, Department of Endocrinology, Tongji Medical College, Huazhong University of Science and Technology, Tongji Hospital, Hubei, P.R. China. Laboratory of ChromosomeandCell Biology, TheRockefeller University, NewYork,NewYork. Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Current Address for P.H. Tan: Whittington Health, Breast Unit, Department of Surgery, The Whittington, Magdala Avenue, London N19 5NF, United Kingdom. Corresponding Authors: Shao-An Xue, University College London Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, United Kingdom. Phone: 44-2077940500; Fax: 44-2074331943; E-mail: [email protected]; and Peng H. Tan, Whittington Health, Breast Unit, Department of Surgery, The Whittington, Magdala Avenue, London N19 5NF, United Kingdom. Phone: 44-2072723070; Fax: 44-2088468081; E-mail: [email protected] doi: 10.1158/0008-5472.CAN-13-1397 2014 American Association for Cancer Research. Cancer Research www.aacrjournals.org OF1 Research. on April 13, 2017. © 2014 American Association for Cancer cancerres.aacrjournals.org Downloaded from Published OnlineFirst September 26, 2014; DOI: 10.1158/0008-5472.CAN-13-1397