Visceral fat adipocytes from obese and colorectal cancer subjects exhibit distinct secretory and ω6 polyunsaturated fatty acid profiles and deliver immunosuppressive signals to innate immunity cells

Abstract

// Manuela Del Cornò 1, * , Massimo D’Archivio 2, * , Lucia Conti 1 , Beatrice Scazzocchio 2 , Rosaria Varì 2 , Gloria Donninelli 1 , Barbara Varano 1 , Stefania Giammarioli 2 , Simone De Meo 1 , Gianfranco Silecchia 3 , Francesco Pennestrì 4 , Roberto Persiani 4 , Roberta Masella 2 , Sandra Gessani 1 1 Departments of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy 2 Departments of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy 3 Department of Medical-Surgical Sciences and Biotecnologies, Sapienza University of Rome, Rome, Italy 4 General Surgery Unit, Catholic University, Rome, Italy * These authors equally contributed to this work Correspondence to: Sandra Gessani, email: sandra.gessani@iss.it Keywords: obesity, adipose tissue, fatty acids, immune cells, colorectal cancer Received: March 04, 2016      Accepted: July 22, 2016      Published: August 01, 2016 ABSTRACT Obesity is a low-grade chronic inflammatory state representing an important risk factor for colorectal cancer (CRC). Adipocytes strongly contribute to inflammation by producing inflammatory mediators. In this study we investigated the role of human visceral fat adipocytes in regulating the functions of innate immunity cells. Adipocyte-conditioned media (ACM) from obese ( n = 14) and CRC (lean, n = 14; obese, n = 13) subjects released higher levels of pro-inflammatory/immunoregulatory factors as compared to ACM from healthy lean subjects ( n = 13). Dendritic cells (DC), differentiated in the presence of ACM from obese and CRC subjects, expressed elevated levels of the inhibitory molecules PD-L1 and PD-L2, and showed a reduced IL-12/IL-10 ratio in response to both TLR ligand- and γδ T lymphocyte-induced maturation. Furthermore, CRC patient-derived ACM inhibited DC-mediated γδ T cell activation. The immunosuppressive signals delivered by ACM from obese and CRC individuals were associated with a pro-inflammatory secretory and ω6 polyunsaturated fatty acid profile of adipocytes. Interestingly, STAT3 activation in adipocytes correlated with dihomo-γlinolenic acid content and was further induced by arachidonic acid, which conversely down-modulated PPARγ. These results provide novel evidence for a cross-talk between human adipocytes and innate immunity cells whose alteration in obesity and CRC may lead to immune dysfunctions, thus setting the basis for cancer development.