Adipocytes affect castration‐resistant prostate cancer cells to develop the resistance to cytotoxic action of NK cells with alterations of PD‐L1/NKG2D ligand levels in tumor cells

Xu, Lanfang; Shen, Meifen; Chen, Xiao; Zhu, Rongying; Yang, Dian; Tsai, Ying Huang; Keng, Peter C.; Chen, Yuhchyau; Lee, Soo Ok

doi:10.1002/pros.23479

Cited by 36 publications

(28 citation statements)

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“…Former in vitro and in vivo studies showed that leptin has a diminishing effect on cytotoxicity and cytokine secretion of NK cells and modulates NK cell surface receptor expression [ 14 , 24 , 25 , 35 ]. The discrepancy between the increased leptin receptor expression in obesity and the altered functionality in NK cells after leptin incubation could be explained by an impaired post-receptor leptin signaling cascade in NK cells [ 14 , 24 , 27 , 35 ]. Besides leptin, other obesity-related metabolites, like adiponectin or IL-6, are shown to influence NK cell functionality [ 15 , 21 , 22 , 27 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies investigated NK cell functionality in obesity. In vitro analyses revealed evidence for an altered cytotoxicity, cytokine secretion, and phenotype of primary NK cells and NK cell lines after incubation with the adipocytokines leptin or adiponectin as well as adipocytokine containing supernatants derived from cultured adipocytes [ 21 – 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Impaired natural killer cell subset phenotypes in human obesity

et al. 2018

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Obesity is associated with alterations in functionality of immune cells, like macrophages and natural killer (NK) cells, leading to an increased risk for severe infections and several cancer types. This study aimed to examine immune cell populations and functional NK cell parameters focusing on NK cell subset phenotypes in normal-weight and obese humans. Therefore, peripheral blood mononuclear cells (PBMCs) were isolated from normal-weight and obese individuals and analyzed by flow cytometry. Results show no significant changes in the frequency of monocytes, B lymphocytes, or NKT cells but a significantly increased frequency of T lymphocytes in obesity. The frequency of total NK cells was unaltered, whereas the number of low cytotoxic CD56bright NK cell subset was increased, and the number of high cytotoxic CD56dim NK cell subset was decreased in obese subjects. In addition, the frequency of CD56bright NK cells expressing the activating NK cell receptor NKG2D as well as intracellular interferon (IFN)-γ was elevated in the obese study group. In contrast, the frequency of NKG2D- and IFN-γ-positive CD56dim NK cells was lower in obesity compared to normal-weight individuals. Moreover, the expression of the activation marker CD69 was decreased in NK cells, which can be attributed to a reduction of CD69-positive CD56dim NK cells in obese subjects. In conclusion, data reveal an impaired NK cell phenotype and NK cell subset alterations in obese individuals. This NK cell dysfunction might be one link to the higher cancer risk and the elevated susceptibility for viral infections in obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impaired natural killer cell subset phenotypes in human obesity

et al. 2018

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“…Results demonstrated a reduced cytotoxicity of ACM-treated human NK cells against prostate cancer cells. This effect has been shown to be primarily mediated via the IL-6 and leptin content in the ACM (126). Furthermore, ACM-treatment of NK cells resulted in a decrease of granzyme-and TRAIL-positive NK cells, but an increase of IFN-γ production, although the effects of ACM seem to be species-specific and depending on the different phases of adipogenesis the ACM was harvested (69,77).…”

Section: Insights About Expression Of Adipokine Receptors On Nk Cellsmentioning

confidence: 99%

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

et al. 2020

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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...

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“…9 Moreover, recent studies indicate that interleukin-6 (IL-6) and leptin secreted by the adipocyte induce PD-L1 expression in cancer cells via activation of the JAK/Stat3 pathway. 10 A switch from white fat to brown fat caused by tumor cells 11 can also promote the direct expression of PD-L1 in adipocytes. 12 Therefore, targeting TAAs may be used to interrupt and eliminate a significant source of nutrients and immune protection for tumor cells.…”

Section: Introductionmentioning

confidence: 99%