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.
Subject(s)
Breast Neoplasms/immunology , Dendritic Cells/metabolism , Receptors, Adiponectin/metabolism , Tumor Escape , Adiponectin/physiology , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Clonal Anergy , Cyclooxygenase 2/metabolism , Cytotoxicity, Immunologic , Disease Progression , Enzyme Activation , Female , Humans , Interleukin-10/metabolism , MAP Kinase Signaling System , Mice, Inbred C57BL , NF-kappa B/metabolism , Neoplasm Transplantation , PPAR gamma/metabolism , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
BACKGROUND: Margin status is the main factor determining local recurrence (LR) after wide excision and radiotherapy for breast cancer. The aim of the study is to evaluate if positive margins are as great a risk factor for LR in node-positive as in node-negative patients, since the major risk in the former group is dissemination and whether there is a correlation between nodal status and margins in relation to prognosis. METHODS: 773 patients underwent WLE and radiotherapy between 1988 and 1992 and were followed-up (> 10 years) to determine LR rates according to margin and nodal status. Margins were assessed by cavity-shave biopsies and the axilla was staged by sampling or clearance. RESULTS: 461 patients were node negative and 312 node positive. In the node-negative group 415 patients had negative margins and 46 positive: LR after > 10 years was 12 % and 28 % respectively. Among the 312 patients in the node positive group, 267 were margin negative and 45 positive; the LR rate was 12 % and 18 % respectively. In the node negative-group there was a statistically significant difference between the positive and the negative margins with higher relapse rate and lower overall survival (p < 0.001), whereas in the node-positive group the equivalent comparison didn't show any statistical difference. CONCLUSION: Although re-excision should be always recommended, in node-negative patients positive margins are associated with a statistically higher LR rate and lower overall survival while in node-positive disease margins might be of less importance in determining prognosis as dissemination is more likely to occur.
