Abstract
Visceral adipose tissue (VAT) is a main site where metabolic and immunologic processes interplay to regulate, at local and systemic level, the inflammatory status and immune response. Obesity-associated inflammation and immune dysfunctions are inextricably linked to tumor but, in spite of intense efforts, the mechanisms underpinning this association remain elusive. In this report, we characterized the profile of VAT-associated and circulating innate lymphocyte and regulatory T (Treg) cell subsets underlying inflammatory conditions, such as obesity and colorectal cancer (CRC). Analysis of NK, NKT-like, γδ T, and Treg cell populations in VAT and blood of healthy lean subjects revealed that CD56hi NK and OX40+ Treg cells are more abundant in VAT with respect to blood. Conversely, CD56dim NK and total Treg cells are most present in the circulation, while γδ T lymphocytes are uniformly distributed in the two compartments. Interestingly, a reduced frequency of circulating activated Treg cells, and a concomitant preferential enrichment of OX40-expressing Treg cells in VAT, were selectively observed in obese (Ob) subjects, and directly correlated with body mass index. Likewise, CRC patients were characterized by a specific enrichment of VAT-associated NKT-like cells. In addition, Ob and CRC-affected individuals shared a significant reduction of the Vγ9Vδ2/γδ T cell ratio at systemic level. The alterations in the relative proportions of Treg and NKT-like cells in VAT were found to correlate with the content of pro- and anti-inflammatory polyunsaturated fatty acids (PUFA), respectively. Overall, these results provide evidence for distinct alterations of the immune cell repertoire in the periphery with respect to the VAT microenvironment that uniquely characterize or are shared by different inflammatory conditions, such as obesity and CRC, and suggest that VAT PUFA composition may represent one of the factors that contribute to shape the immune phenotypes.
Highlights
Obesity has become a major threat to public health because of its high global prevalence and association with an increased risk of developing chronic diseases
We initially quantified the frequency of innate lymphocyte populations and Treg cells in homeostatic conditions assessing matched Visceral adipose tissue (VAT) stromal vascular fraction (SVF) and peripheral blood (PB) samples collected from healthy lean subjects
In keeping with previously published data highlighting that NKT cells are one of the adipose tissue (AT) resident cell subsets, a general enrichment of the CD3+CD56+ NKT-like cell population was found in VAT SVF (Figure 1C) as compared to PB
Summary
Obesity has become a major threat to public health because of its high global prevalence and association with an increased risk of developing chronic diseases. Race, dietary habits, or smoking history, obesity is one of the risk factors for several types of cancer including colorectal cancer (CRC) [2, 3] and contributes to 3–20% of cancer deaths in western populations [4, 5]. Obesity-associated low-grade chronic inflammation is considered a main risk factor for adiposity-related pathologies including CRC [8]. A well-established link between CRC and chronic inflammation, sustained by tumor cell-extrinsic as well as -intrinsic pathways, has been recognized in multiple settings. Dietary components are recognized as important modulators of inflammation, and healthy/unhealthy diets have been associated with reduced/increased CRC prevalence, respectively [9]. Dietary intake has been directly linked to PUFA composition of VAT [12] and CRC cell growth as well as tumor progression in mouse models [13]. VAT might represent the initial place where PUFA-related dietary information is transferred to the immune system and contributes to regulate homeostasis
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