Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

Abstract

Obesity is accompanied by a systemic chronic low-grade inflammation as well as dysfunctions of several innate and adaptive immune cells. Recent findings emphasize an impaired functionality and phenotype of natural killer (NK) cells under obese conditions. This review provides a detailed overview on research related to overweight and obesity with a particular focus on NK cells. We discuss obesity-associated alterations in subsets, distribution, phenotype, cytotoxicity, cytokine secretion, and signaling cascades of NK cells investigated in vitro as well as in animal and human studies. In addition, we provide recent insights into the effects of physical activity and obesity-associated nutritional factors as well as the reduction of body weight and fat mass on NK cell functions of obese individuals. Finally, we highlight the impact of impaired NK cell physiology on obesity-associated diseases, focusing on the elevated susceptibility for viral infections and increased risk for cancer development and impaired treatment response.NK cells are large granular lymphocytes that mediate rapid innate immunity against viruses, bacteria, parasites, and tumor cells without prior sensitization. NK cells primarily develop and mature in the bone marrow, migrate through the bloodstream, and seed into secondary lymphoid organs, like thymus, spleen, and lymph nodes as well as in other peripheral tissues, like lung, liver, kidney, uterus, and the gastrointestinal tract (23). In blood, NK cells represent 1-6% of all leukocytes and comprise up to 15% of human peripheral blood mononuclear cells (PBMCs). Human NK cells have been defined by the expression of adhesion molecule CD56 and by the absence of the T cell marker CD3. Based on their expression level of CD56 and the Fcγ receptor CD16, NK cells are subdivided into different subpopulations. The two major and classically defined subsets are the CD56 dim CD16 bright NK cells and the CD56 bright CD16 dim/neg NK cells. CD56 dim CD16 bright NK cells represent about 90% of all NK cells and are predominantly found in peripheral blood (24). They are mostly responsible for cytotoxic activity and target cell killing but are also a source of pro-inflammatory Abbreviations: ACM, adipocyte-conditioned media; Adamts3, a disintegrin-like and metallopeptidase with thrombospondin type 1 motif, 3; AdipoR, adiponectin receptor; Anxa8, annexin A8; AT, adipose tissue; Bax, Bcl-2-associated X protein; Bcl, B-cell lymphoma; BMI, body mass index; CCR, CC chemokine receptor; Csf1r, colony stimulating factor 1 receptor; CX3CR1, C-X3-C-motif chemokine receptor 1; DNAM-1, DNAX accessory molecule-1; ESR, estrogen receptor; FasL, Fas ligand; IFN-γ, interferon; GM-CSF; granulocyte macrophage colony-stimulating factor; H6pd, hexose-6-phosphate dehydrogenase; Hk2, hexokinase 2; IL, interleukinIL-6R; interleukin-6 receptor; Il18rap, interleukin 18 receptor accessory protein; IP-10, interferon gamma-induced protein 10; JAK, Janus kinase; KIR, killer immunoglobulin-like receptor; Klra1, killer lectin-like receptor subfamil...

Characterization of Surface Receptor Expression and Cytotoxicity of Human NK Cells and NK Cell Subsets in Overweight and Obese Humans

“…Nevertheless, the link between obesity and cancer susceptibility is still elusive. The altered phenotype and functionality of NK cells in obese individuals have been discussed to contribute to the increased cancer risk in obesity (22,61). However, the available data on the meaning of functional NK cell receptors in dependence on body weight is insufficient.…”

“…Interestingly, animal studies have demonstrated that the NK cell phenotype is strongly influenced by the metabolic environment, as obese-related alterations could be normalized by NK cell transfer of obese rats into normal weight rats (106). In addition, body weight reduction of obese individuals by dietary intervention, physical activity or bariatric surgery can re-activate altered NK cell functionality (22,100,107,108). Therefore, prevention of overweight and fat mass reduction in obesity by physical training or caloric restriction may attenuate the risk for obesity-associated cancer types by improving the NK cell function.…”

COVID-19 and Obesity: Dangerous Liaisons

“…Obesity induces a state of moderate chronic inflammation (Figure 1), IL-6 and TNF-α are consistently increased in circulation of obese humans and mouse models [49,50]. It induces an inflammatory state through the increase of macrophage infiltration into adipose tissue, the polarization state of macrophages and the augmentation of cytokines and chemokines [51][52][53]. IL-6 and STAT3 signaling act as critical determinants for obese models [49,50], and form a feed-forward loop.…”

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

“…Next to mechanical issues, obesity is accompanied by a systemic, chronic low-grade inflammation as well as dysfunctions of several innate and adaptive immune cells. Recent findings emphasize an impaired functionality and phenotype of natural killer (NK) cells under obese conditions (Bähr et al, 2020). Elevated circulating levels of PGE2 have been observed in obese individuals (Fain et al, 2002;Pawelzik et al, 2019).…”