Tumour growth and dissemination is largely dependent on nutrient availability. It has recently emerged that the tumour microenvironment is rich in a diverse array of lipids that increase in abundance ...with tumour progression and play a role in promoting tumour growth and metastasis. Here, we describe the pro-tumorigenic roles of lipid uptake, metabolism and synthesis and detail the therapeutic potential of targeting lipid metabolism in cancer. Additionally, we highlight new insights into the distinct immunosuppressive effects of lipids in the tumour microenvironment. Lipids threaten an anti-tumour environment whereby metabolic adaptation to lipid metabolism is linked to immune dysfunction. Finally, we describe the differential effects of commondietary lipids on cancer growth which may uncover a role for specific dietary regimens in association with traditional cancer therapies. Understanding the relationship between dietary lipids, tumour, and immune cells is important in the context of obesity which may reveal a possibility to harness the diet in the treatment of cancers.
•Lipid metabolism plays a key role in the tumour microenvironment.•Lipid metabolism in both the tumour and immune cells can promote tumour progression.•Obesity is associated with impaired immune ...surveillance.•Lipid metabolism may link obesity and increased cancer risk.
Obesity is a major risk factor for metabolic disease, with white adipose tissue (WAT) inflammation emerging as a key underlying pathology. Alongside its major role in energy storage, WAT is an ...important endocrine organ, producing many bioactive molecules, termed adipokines, which not only serve as regulators of systemic metabolism, but also possess immunoregulatory properties. Furthermore, WAT contains a unique immune cell repertoire, including an accumulation of leukocytes that are rare in other locations. These include alternatively activated macrophages, invariant natural killer T cells, and regulatory T cells. Disruption of resident adipose leukocyte homeostasis contributes to obesity-associated inflammation and consequent metabolic disorder. Despite many recent advances in this new field of immuno-metabolism, fundamental questions of why and how inflammation arises as obesity develops are not yet fully understood. Exploring the distinct immune system of adipose tissue is fundamental to our understanding of the endocrine as well as immune systems. In this review, we discuss the roles of adipose tissue leukocytes in the transition to obesity and progression of inflammation and highlight potential anti-inflammatory therapies for combating obesity-related pathology.
Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications
. Epidemiological studies have ...suggested that diabetes is also linked to an increased risk of cancer
. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.
Invariant natural killer T cells (iNKT cells) are lipid-sensing innate T cells that are restricted by the antigen-presenting molecule CD1d and express the transcription factor PLZF. iNKT cells ...accumulate in adipose tissue, where they are anti-inflammatory, but the factors that contribute to their anti-inflammatory nature, as well as their targets in adipose tissue, are unknown. Here we found that iNKT cells in adipose tissue had a unique transcriptional program and produced interleukin 2 (IL-2) and IL-10. Unlike other iNKT cells, they lacked PLZF but expressed the transcription factor E4BP4, which controlled their IL-10 production. The adipose iNKT cells were a tissue-resident population that induced an anti-inflammatory phenotype in macrophages and, through the production of IL-2, controlled the number, proliferation and suppressor function of regulatory T cells (Treg cells) in adipose tissue. Thus, iNKT cells in adipose tissue are unique regulators of immunological homeostasis in this tissue.
Adipose tissue is a critical regulator of systemic metabolism and normal bodily homeostasis. Recently, the immune system has been implicated in the regulation of adipose tissue homeostasis and ...function. Here, we highlight new insights into the distinct phenotypes and functions of adipose resident leukocytes, including a growing body of work on their role in adipose tissue remodeling and thermogenesis. We discuss how the protective capacity of the adipose immune system can be diminished during obesity, where immune cells promote sterile inflammation leading to insulin resistance. Understanding the role of adipose immune cells across different physiological states and processes is important in understanding the full breadth of adipose immunity and the possibilities to harness immune cells in fat tissue for the treatment of chronic metabolic conditions, including obesity.
The human and murine adipose immune system is enriched in innate immune cells, including innate lymphoid cells and unconventional T cells such as invariant natural killer T (iNKT) cells, γδ T cells, and mucosal-associated invariant T (MAIT) cells (humans). Many of these cells are tissue resident with little recirculation occurring between adipose and peripheral populations.Adipose immune cells have atypical phenotypes adapted to the unusual, lipid-rich adipose environment. Many immune cells express genes associated with lipid handling and metabolism, such as peroxisome proliferator receptor (PPAR)γ, and display alternative or regulatory polarization; for example, adipose iNKT cells produce interleukin (IL)-10 and IL-2 rather than interferon (IFN)γ and IL-4 after stimulation.In mice, the adipose immune system plays a crucial role in maintaining local homeostasis and contributes to the regulation of systemic metabolism. It also performs many noncanonical functions, such as regulating adaptative thermogenesis.In murine and human obesity, the adipose immune system becomes dysregulated. Many of the resident regulatory populations become depleted and are replaced by inflammatory cells as a result of phenotypic switching of resident adipose immune cells or the infiltration of more inflammatory immune cells from the periphery.
Obese individuals who smoke have a 14 year reduction in life expectancy. Both obesity and smoking are independently associated with increased risk of malignancy. Natural killer cells (NK) are ...critical mediators of anti-tumour immunity and are compromised in obese patients and smokers. We examined whether NK cell function was differentially affected by cigarette smoke in obese and lean subjects.
Clinical data and blood were collected from 40 severely obese subjects (BMI>40 kg/m(2)) and 20 lean healthy subjects. NK cell levels and function were assessed using flow cytometry and cytotoxicity assays. The effect of cigarette smoke on NK cell ability to kill K562 tumour cells was assessed in the presence or absence of the adipokines leptin and adiponectin. NK cell levels were significantly decreased in obese subjects compared to lean controls (7.6 vs 16.6%, p = 0.0008). NK function was also significantly compromised in obese patients (30% +/- 13% vs 42% +/-12%, p = 0.04). Cigarette smoke inhibited NK cell ability to kill tumour cell lines (p<0.0001). NK cells from obese subjects were even more susceptible to the inhibitory effects of smoke compared to lean subjects (33% vs 28%, p = 0.01). Cigarette smoke prevented NK cell activation, as well as perforin and interferon-gamma secretion upon tumour challenge. Adiponectin but not leptin partially reversed the effects of smoke on NK cell function in both obese (p = 0.002) and lean controls (p = 0.01).
Obese subjects have impaired NK cell activity that is more susceptible to the detrimental effects of cigarette smoke compared to lean subjects. This may play a role in the increase of cancer and infection seen in this population. Adiponectin is capable of restoring NK cell activity and may have therapeutic potential for immunity in obese subjects and smokers.
With the emerging obesity pandemic, identifying those who appear to be protected from adverse consequences such as type 2 diabetes and certain malignancies will become important. We propose that the ...circulating immune system plays a role in the development of these comorbidities. Clinical data and blood samples were collected from 52 patients with severe obesity attending a hospital weight‐management clinic and 11 lean healthy controls. Patients were classified into metabolically “healthy obese” (n = 26; mean age 42.6 years, mean BMI 46.8 kg/m2) or “unhealthy obese” (n = 26; mean age 45 years, mean BMI 47.5 kg/m2) groups, based upon standard cutoff points for blood pressure, lipid profile, and fasting glucose. Circulating lymphoid populations and phenotypes were assessed by flow cytometry. Obese patients had significantly less circulating natural killer (NK) and cytotoxic T lymphocytes (CTL) compared to lean controls. There were significantly higher levels of NK cells and CTLs in the healthy obese group compared to the unhealthy obese group (NK: 11.7% vs. 6.5%, P < 0.0001, CD8 13.4% vs. 9.3%, P = 0.04), independent of age and BMI and these NK cells were also less activated in the healthy compared to the unhealthy group (CD69, 4.1% vs. 11.8%, P = 0.03). This is the first time that quantitative differences in the circulating immune system of obese patients with similar BMI but different metabolic profiles have been described. The significantly higher levels of CTLs and NK cells, which express fewer inhibitory molecules, could protect against malignancy, infection, and metabolic disease seen in obesity.
γδ T cells are a small population of mostly tissue‐resident lymphocytes, with both innate and adaptive properties. These unique features make them particularly attractive candidates for the ...development of new cellular therapy targeted against tumor development. Nevertheless, γδ T cells may play dual roles in cancer, promoting cancer development on the one hand, while participating in antitumor immunity on the other hand. In mice, γδ T‐cell subsets preferentially produce IL‐17 or IFN‐γ. While antitumor functions of murine γδ T cells can be attributed to IFN‐γ+ γδ T cells, recent studies have implicated IL‐17+ γδ T cells in tumor growth and metastasis. However, in humans, IL‐17‐producing γδ T cells are rare and most studies have attributed a protective role to γδ T cells against cancer. In this review, we will present the current knowledge and most recent findings on γδ T‐cell functions in mouse models of tumor development and human cancers. We will also discuss their potential as cellular immunotherapy against cancer.
γδ T cells play crucial roles in antitumor immunity but have been also linked to tumor growth. Due to their innate and adaptive features, γδ T cells also constitute attractive candidates for newly developing cancer immunotherapy. In this review, we discuss the latest findings and future directions of this conflicting but highly promising field.
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