Natürliche Killerzellen, Adipositas & Tumorgenese

Zusammenfassung

Die Prävalenz für Adipositas nimmt sowohl in Industrienationen als auch in Entwicklungsländern stetig zu. So hat sich die Zahl der fettleibigen Menschen in den vergangenen 30 Jahren nahezu verdoppelt. Nach Schätzungen der WHO sind weltweit 1,5 Milliarden Menschen übergewichtig (BMI ≥ 25 kg/m²); 500 Millionen Menschen gelten bereits als adipös (BMI ≥ 30 kg/m²). In Deutschland sind entsprechend den Angaben des Robert-Koch-Institutes 67,1 % der Männer und 53,0 % der Frauen übergewichtig; rund 23 % aller Erwachsenen sind adipös. Neben Adipositas-assoziierten Folge- oder Begleiterkrankungen, wie Diabetes mellitus Typ 2, kardiovaskuläre und degenerative Erkrankungen und Fettstoffwechselstörungen ist auch die Prävalenz für die Entstehung von Karzinomen durch Adipositas erhöht. Insbesondere häufig auftretende Krebsarten wie postmenopausaler Brustkrebs und Darmkrebs stellen ein enormes medizinisches, soziales und gesundheitspolitisches Problem dar. Das veränderte metabolisch-immunologische Gleichgewicht, infolge von Übergewicht und Adipositas, führt zu Funktionsverlusten von Immunzellen des angeborenen und erworbenen Immunsystems, einschließlich den Natürlichen Killerzellen (NK-Zellen) als Vertreter der angeborenen Immunität. Das heutige Wissen über die Funktionsveränderungen von NK-Zellen im adipösen Organismus und deren Konsequenz für die Entstehung und Pathogenese von Tumoren wird in dieser Übersichtsarbeit dargestellt. Präklinische Interventionen mit beeindruckenden zellbiologischen Effekten werden diskutiert.

Abstract

The prevalence of obesity is rising in industrial nations as well as in developing countries. The number of obese individuals has doubled during the last 30 years. Estimations by the WHO suppose that 1.5 billion humans are overweight (BMI ≥ 25 kg/m²) and 500 million humans are obese (BMI ≥ 30 kg/m²). In Germany, 53.0 % of women and 67.1 % of man are overweight, whereas 23 % of all adults can be categorized into the obese group as declared by the Robert-Koch-Institute. In addition to obesity-associated secondary disorders and comorbidities such as type 2 diabetes, cardiovascular and degenerative diseases and alterations of metabolism, the development of several cancer types is significantly associated with obesity. In particular, frequent cancer types of breast and colon tissues are an enormous medical, social and health policy issue. The metabolic-immunological balance is altered in consequence of obesity. This leads to functional impairments of immune cells, both of the adaptive as well as innate immune system including Natural killer (NK) cells as part of the innate immunity. Current knowledge of the consequences of obesity for NK cell functionality in relation to the development and pathology of cancer will be outlined in this review. Pre-clinical interventions with impressive cell biological effects will be discussed.

Schlüsselwörter

Natürliche Killerzellen - Fettgewebe - Übergewicht - Krebs - Intervention

Key words

Natural killer cells - adipose tissue - obesity - cancer - intervention

• Literatur

• 1 Behrens G, Gredner T, Stock C. et al. Krebs durch Übergewicht, geringe körperliche Aktivität und ungesunde Ernährung: Schätzung der attributablen Krebslast in Deutschland. Deutsches Ärzteblatt international 2018; 2018: 579-85
• 2 Himbert C, Delphan M, Scherer D. et al. Signals from the Adipose Microenvironment and the Obesity-Cancer Link-A Systematic Review. Cancer Prev Res (Phila) 2017; 10: 494-506 doi:10.1158/1940–6207.CAPR-16–0322
• 3 Ackerman SE, Blackburn OA, Marchildon F. et al. Insights into the Link Between Obesity and Cancer. Curr Obes Rep 2017; 6: 195-203 doi:10.1007/s13679–017–0263-x
• 4 Francisco V, Pino J, Gonzalez-Gay MA. et al. Adipokines and inflammation: is it a question of weight?. Br J Pharmacol 2018; 175: 1569-1579 doi:10.1111/bph.14181
• 5 Laue T, Wrann CD, Hoffmann-Castendiek B. et al. Altered NK cell function in obese healthy humans. BMC Obes 2015; 2: 1 doi:10.1186/s40608–014–0033–1
• 6 Nave H, Mueller G, Siegmund B. et al. Resistance of Janus kinase-2 dependent leptin signaling in natural killer (NK) cells: A novel mechanism of NK cell dysfunction in diet-induced obesity. Endocrinology 2008; 149: 3370-3378 doi:10.1210/en.2007–1516
• 7 Choe SS, Huh JY, Hwang IJ. et al. Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders. Front Endocrinol (Lausanne) 2016; 7: 30 doi:10.3389/fendo.2016.00030
• 8 Esteve Ràfols M. Adipose tissue: cell heterogeneity and functional diversity. Endocrinol Nutr 2014; 61: 100-112 doi:10.1016/j.endonu.2013.03.011
• 9 Francisco V, Pino J, Campos-Cabaleiro V. et al. Obesity, Fat Mass and Immune System: Role for Leptin. Front Physiol 2018; 9: 640 doi:10.3389/fphys.2018.00640
• 10 Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. BJN 2004; 92: 347 doi:10.1079/BJN20041213
• 11 Zhang Y, Proenca R, Maffei M. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-432 doi:10.1038/372425a0
• 12 Scotece M, Conde J, López V. et al. Adiponectin and leptin: new targets in inflammation. Basic Clin Pharmacol Toxicol 2014; 114: 97-102 doi:10.1111/bcpt.12109
• 13 Münzberg H, Morrison CD. Structure, production and signaling of leptin. Metab Clin Exp 2015; 64: 13-23 doi:10.1016/j.metabol.2014.09.010
• 14 Gilbert CA, Slingerland JM. Cytokines, obesity, and cancer: new insights on mechanisms linking obesity to cancer risk and progression. Annu Rev Med 2013; 64: 45-57 doi:10.1146/annurev-med-121211–091527
• 15 Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm 2013; 2013: 139239 doi:10.1155/2013/139239
• 16 Luo Y, Liu M. Adiponectin: a versatile player of innate immunity. J Mol Cell Biol 2016; 8: 120-128 doi:10.1093/jmcb/mjw012
• 17 Wensveen FM, Valentić S, Šestan M. et al. The “Big Bang” in obese fat: Events initiating obesity-induced adipose tissue inflammation. Eur J Immunol 2015; 45: 2446-2456 doi:10.1002/eji.201545502
• 18 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444: 860-867 doi:10.1038/nature05485
• 19 Emilsson V, Thorleifsson G, Zhang B. et al. Genetics of gene expression and its effect on disease. Nature 2008; 452: 423-428 doi:10.1038/nature06758
• 20 Huh JY, Park YJ, Ham M. et al. Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol Cells 2014; 37: 365-371 doi:10.14348/molcells.2014.0074
• 21 Beaulieu AM. Memory responses by natural killer cells. J Leukoc Biol. 2018 doi:10.1002/JLB.1RI0917–366 R
• 22 Vivier E, Artis D, Colonna M. et al. Innate Lymphoid Cells: 10 Years On. Cell 2018; 174: 1054-1066 doi:10.1016/j.cell.2018.07.017.
• 23 Paul S, Lal G. The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy. Front Immunol 2017; 8: 1124 doi:10.3389/fimmu.2017.01124
• 24 Kim N, Kim HS. Targeting Checkpoint Receptors and Molecules for Therapeutic Modulation of Natural Killer Cells. Front Immunol 2018; 9: 2041 doi:10.3389/fimmu.2018.02041
• 25 Hayashi T, Imai K, Morishita Y. et al. Identification of the NKG 2D haplotypes associated with natural cytotoxic activity of peripheral blood lymphocytes and cancer immunosurveillance. Cancer Res 2006; 66: 563-570 doi:10.1158/0008–5472.CAN-05–2776
• 26 Kabalak G, Thomas RM, Martin J. et al. Association of an NKG 2D gene variant with systemic lupus erythematosus in two populations. Hum Immunol 2010; 71: 74-78 doi:10.1016/j.humimm.2009.09.352
• 27 Lautenbach A, Wrann CD, Jacobs R. et al. Altered phenotype of NK cells from obese rats can be normalized by transfer into lean animals. Obesity (Silver Spring) 2009; 17: 1848-1855 doi:10.1038/oby.2009.140
• 28 Viel S, Besson L, Charrier E. et al. Alteration of Natural Killer cell phenotype and function in obese individuals. Clin Immunol 2017; 177: 12-17 doi:10.1016/j.clim.2016.01.007
• 29 O’Shea D, Cawood TJ, O’Farrelly C. et al. Natural killer cells in obesity: Impaired function and increased susceptibility to the effects of cigarette smoke. PLoS ONE 2010; 5: e8660 doi:10.1371/journal.pone.0008660
• 30 Bähr I, Jahn J, Zipprich A. et al. Impaired natural killer cell subset phenotypes in human obesity. Immunol Res 2018; 66: 234-244 doi:10.1007/s12026–018–8989–4
• 31 Theurich S, Tsaousidou E, Hanssen R. et al. IL-6/Stat3-Dependent Induction of a Distinct, Obesity-Associated NK Cell Subpopulation Deteriorates Energy and Glucose Homeostasis. Cell Metab 2017; 26: 171-184.e6 doi:10.1016/j.cmet.2017.05.018
• 32 Cifaldi L, Prencipe G, Caiello I. et al. Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis & rheumatology (Hoboken, N.J.) 2015; 67: 3037-3046 doi:10.1002/art.39295
• 33 Jasinski-Bergner S, Büttner M, Quandt D. et al. Adiponectin and Its Receptors Are Differentially Expressed in Human Tissues and Cell Lines of Distinct Origin. Obes Facts 2017; 10: 569-583 doi:10.1159/000481732
• 34 Keustermans G, van der Heijden LB, Boer B. et al. Differential adipokine receptor expression on circulating leukocyte subsets in lean and obese children. PLoS ONE 2017; 12: e0187068 doi:10.1371/journal.pone.0187068
• 35 Tian Z, Sun R, Wei H. et al. Impaired natural killer (NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator in NK cell development and activation. Biochemical and Biophysical Research Communications 2002; 298: 297-302 doi:10.1016/S0006–291X(02)02462–2
• 36 Oswald J, Büttner M, Jasinsky-Bergner S. et al. Leptin affects filopodia and cofilin in NK-92 cells in a dose- and time-dependent manner. Eur J Histochem 2018; 62: 2848 doi:10.4081/ejh.2018.2848
• 37 Wrann CD, Laue T, Hubner L. et al. Short-term and long-term leptin exposure differentially affect human natural killer cell immune functions. Am J Physiol Endocrinol Metab 2012; 302: E108-116 doi:10.1152/ajpendo.00057.2011
• 38 Bähr I, Goritz V, Doberstein H. et al. Diet-Induced Obesity Is Associated with an Impaired NK Cell Function and an Increased Colon Cancer Incidence. J Nutr Metab 2017; 2017: 4297025 doi:10.1155/2017/4297025
• 39 Lamas B, Goncalves-Mendes N, Nachat-Kappes R. et al. Leptin modulates dose-dependently the metabolic and cytolytic activities of NK-92 cells. J Cell Physiol 2013; 228: 1202-1209 doi:10.1002/jcp.24273
• 40 Huebner L, Engeli S, Wrann CD. et al. Human NK cell subset functions are differentially affected by adipokines. PLoS ONE 2013; 8: e75703 doi:10.1371/journal.pone.0075703
• 41 Zhao Y, Sun R, You L. et al. Expression of leptin receptors and response to leptin stimulation of human natural killer cell lines. Biochemical and Biophysical Research Communications 2003; 300: 247-252 doi:10.1016/S0006–291X(02)02838–3
• 42 Farooqi IS, Wangensteen T, Collins S. et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 2007; 356: 237-247 doi:10.1056/NEJMoa063988
• 43 Lord GM, Matarese G, Howard JK. et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998; 394: 897-901 doi:10.1038/29795
• 44 Fridman WH, Zitvogel L, Sautès-Fridman C. et al. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 2017; 14: 717-734 doi:10.1038/nrclinonc.2017.101
• 45 Sharma P, Kumar P, Sharma R. Natural Killer Cells – Their Role in Tumour Immunosurveillance. J Clin Diagn Res 2017; 11: BE01-BE05 doi:10.7860/JCDR/2017/26748.10469
• 46 Guillerey C. Roles of cytotoxic and helper innate lymphoid cells in cancer. Mamm Genome; 2018 doi:10.1007/s00335–018–9781–4
• 47 Rocca YS, Roberti MP, Juliá EP. et al. Phenotypic and Functional Dysregulated Blood NK Cells in Colorectal Cancer Patients Can Be Activated by Cetuximab Plus IL-2 or IL-15. Front Immunol 2016; 7: 413 doi:10.3389/fimmu.2016.00413
• 48 Guillamón CF, Martínez-Sánchez MV, Gimeno L. et al. NK cell education in tumor immune surveillance: DNAM-1/KIR receptor ratios as predictive biomarkers for solid tumor outcome. Cancer Immunol Res; 2018 doi:10.1158/2326–6066.CIR-18–0022
• 49 Spielmann J, Hanke J, Knauf D. et al. Significantly enhanced lung metastasis and reduced organ NK cell functions in diet-induced obese rats. BMC Obes 2017; 4: 24 doi:10.1186/s40608–017–0161–5
• 50 Preethy S, Dedeepiya VD, Senthilkumar R. et al. Natural killer cells as a promising tool to tackle cancer-A review of sources, methodologies, and potentials. Int Rev Immunol 2017; 36: 220-232 doi:10.1080/08830185.2017.1284209
• 51 Fang F, Xiao W, Tian Z. NK cell-based immunotherapy for cancer. Semin Immunol 2017; 31: 37-54 doi:10.1016/j.smim.2017.07.009
• 52 Liang S, Xu K, Niu L. et al. Comparison of autogeneic and allogeneic natural killer cells immunotherapy on the clinical outcome of recurrent breast cancer. Onco Targets Ther 2017; 10: 4273-4281 doi:10.2147/OTT.S139986
• 53 Blair SN. Influences of Cardiorespiratory Fitness and Other Precursors on Cardiovascular Disease and All-Cause Mortality in Men and Women. JAMA 1996; 276: 205 doi:10.1001/jama.1996.03540030039029
• 54 Lynch J. Moderately Intense Physical Activities and High Levels of Cardiorespiratory Fitness Reduce the Risk of Non-Insulin-Dependent Diabetes Mellitus in Middle-aged Men. Arch Intern Med 1996; 156: 1307 doi:10.1001/archinte.1996.00440110073010
• 55 Evenson KR, Stevens J, Cai J. et al. The effect of cardiorespiratory fitness and obesity on cancer mortality in women and men. Med Sci Sports Exerc 2003; 35: 270-277 doi:10.1249/01.MSS.0000053511.02356.72
• 56 Katzmarzyk PT, Church TS, Blair SN. Cardiorespiratory fitness attenuates the effects of the metabolic syndrome on all-cause and cardiovascular disease mortality in men. Arch Intern Med 2004; 164: 1092-1097 doi:10.1001/archinte.164.10.1092
• 57 Barlow CE, LaMonte MJ, Fitzgerald SJ. et al. Cardiorespiratory fitness is an independent predictor of hypertension incidence among initially normotensive healthy women. Am J Epidemiol 2006; 163: 142-150 doi:10.1093/aje/kwj019
• 58 Ito H, Ohshima A, Tsuzuki M. et al. Effects of Increased Physical Activity and Mild Calorie Restriction on Heart Rate Variability in Obese Women. Jpn Heart J 2001; 42: 459-469 doi:10.1536/jhj.42.459
• 59 Amati F, Dubé JJ, Shay C. et al. Separate and combined effects of exercise training and weight loss on exercise efficiency and substrate oxidation. J Appl Physiol 2008; 105: 825-831 doi:10.1152/japplphysiol.90384.2008
• 60 Jahn J, Spielau M, Brandsch C. et al. Decreased NK cell functions in obesity can be reactivated by fat mass reduction. Obesity (Silver Spring) 2015; 23: 2233-2241 doi:10.1002/oby.21229
• 61 Moulin CM, Marguti I, Peron JPS. et al. Bariatric surgery reverses natural killer (NK) cell activity and NK-related cytokine synthesis impairment induced by morbid obesity. Obes Surg 2011; 21: 112-118 doi:10.1007/s11695–010–0250–8
• 62 Barra NG, Fan IY, Gillen JB. et al. High Intensity Interval Training Increases Natural Killer Cell Number and Function in Obese Breast Cancer-challenged Mice and Obese Women. J Cancer Prev 2017; 22: 260-266 doi:10.15430/JCP.2017.22.4.260
• 63 Pedersen L, Idorn M, Olofsson GH. et al. Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution. Cell Metab 2016; 23: 554-562 doi:10.1016/j.cmet.2016.01.011
• 64 Shade ED, Ulrich CM, Wener MH. et al. Frequent intentional weight loss is associated with lower natural killer cell cytotoxicity in postmenopausal women: possible long-term immune effects. J Am Diet Assoc 2004; 104: 903-912 doi:10.1016/j.jada.2004.03.018