Epidemiological studies have indicated that obesity is associated with a higher risk for certain cancers caused by elevated levels of adipocyte-derived hormones. Leptin, one such hormone produced by adipocytes, is a major regulator of metabolism and has also been shown to modulate immunity. However, its role in regulating human natural killer (NK) cell functions is largely unknown. Here, we show that the leptin receptor (Ob-R) is expressed on 5% of NK cells isolated from blood donors, as measured with flow cytometry, and expression of the signal-transducing long form of the leptin receptor Ob-Rb was confirmed with quantitative PCR. The Ob-R+ subpopulation displayed a lower expression of CD16, a cell surface receptor mediating antibody-dependent activation. Short-term stimulation with leptin increased IFNγ secretion, CD69 activation marker expression, and cytotoxic lysis of tumor cells; this was mediated by an improved conjugate forming between NK cells and tumor cells as well as higher expression of tumor necrosis factor-related apoptosis-inducing ligand. On the contrary, long-term incubation with leptin significantly impaired these NK cell immune functions and decreased cell proliferation. In addition, phosphorylation of Jak-2 after leptin stimulation was reduced in peripheral mononuclear blood cells from obese humans compared with normal-weight controls. NK cells represent an immune cell population that is crucial for an effective antitumor response. Here, we show that long-term exposure to leptin, similarly to the situation in obese individuals with elevated serum leptin levels, significantly impairs integral parts of NK cell immune functions, possibly linking leptin to increased cancer susceptibility in obesity.

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Key words: Fischer 344 rat; MADB106 adenocarcinoma; lung metastasis; natural killer (NK) cell; NK cell depletion; monocytes; Tlymphocytes; immunohistochemistryThe initial sequence and early kinetics within minutes and hours of host defense mechanism against metastatic cells are widely unknown. Leukocyte recruitment at sites of tumor is presently investigated in a time frame of several hours and days. 1 A better understanding of the processes and the cellular components constituting the very early first line of tumor defense in vivo/in situ is needed to unravel the mechanisms of clearance and control of organ metastases.Within hours, tumor cells are rapidly "trapped" to their target organs, such as the lungs. During these early time points a nonspecific "clearance rate" of i.v. injected cells from the lungs has originally been shown by Fidler 2 and since reproduced by others. 3,4 These data indicate that during the first several hours after i.v. injection of tumor cells, the lungs clear themselves from non-specifically trapped tumor cells, until at Day 2-5 preferently those tumor cells remain in the lungs that are suspected to produce lung metastases. 2,5 The rate of clearance, however, seems to be increased when tumor cell-binding endothelial cell adhesion molecules are blocked with adhesion-inhibiting antibodies, indicating a close relation between clearance and the expression of particular endothelial cell adhesion molecules. 1 In addition to these functional effects of cell adhesion molecules in the initial "non-specific" tumor cell trapping, also cell-mediated processes might play a role in determining the initial clearance rate of target organs. At least for natural killer (NK) cell dependent tumor models such as the B16 and the MADB106 cell lines a close relationship between NK cell activity exclusively during the initial 24 hr of host defense and the final disease outcome has been demonstrated. At least 70% of MADB106 tumor cells are destroyed in vivo during the first 1-5 hr after injection 4,6 illustrating that the early host defense response against this tumor cell line is crucial. Recent studies demonstrate that stress hormones such as adrenaline modulate the lung retention of MADB106 tumor cells even within minutes. 7 Thus, these data suggest that detailed time kinetic studies of the cellular changes within the first minutes and hours will provide new insights into specific mechanism determining the initial clearance rate of tumor cells in target organs and for the interaction of different leukocyte subsets in the early surveillance of metastasis.To monitor rapid and specific cellular changes within the lungs as a target organ for metastases detailed studies on the interaction of tumor cells with immune cells in situ were required. The present approach combines immunohistochemic methods with vital dye labeling techniques and takes advantage of the visualization and quantification of effector-like cells that co-localized with CFSE (5-(and -6)-carboxyfluorescein diacetate succinimidyl ester) positive MA...

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