Influence of bodyweight on receptor expression and cytotoxicity of primary human natural killer cells against obesity-associated cancers

Introduction:

Overweight and obesity pose a rapidly growing health problem worldwide. Obesity is identified as a major risk factor for many cancer diseases, e.g. colorectal cancer and postmenopausal breast cancer. In the early phase of cancer development and metastasis, natural killer (NK) cells are the central active component of a host's immune system. NK cells express a variety of activating and inhibitory receptors to recognize target cells and to regulate their response. Previous studies demonstrated impaired NK cell functions in obese individuals, but underlying pathophysiological mechanisms remain unclear. Therefore, the present study aimed to investigate the relation between bodyweight and NK cell receptor expression as well as NK cell cytotoxicity against tumor cells in humans.

Methods:

Peripheral blood mononuclear cells (PBMCs) were isolated from buffy coats of blood donors with different body mass indexes (normal weight: BMI 18.5 – 24.9 kg/m²; overweight: BMI 25 – 29.9 kg/m²; obese: BMI ≥30 kg/m²; n = 13 – 17). Subsequently, NK cells were separated from PBMCs by magnetic activated cell sorting. In the following, NK cell cytotoxicity against the human colon cancer cell line DLD-1 and the human breast cancer cell line MCF-7 was measured by a real-time cytotoxicity assay via the iCELLigence system. In addition, PBMCs of identical buffy coat donors were used for flow cytometry to analyze the expression pattern of NK cell receptors on two different NK cell subset populations in dependence on bodyweight.

Results:

Real-time cytotoxicity assays using DLD-1 and MCF-7 target cells revealed a decreased cytolytic activity of primary human NK cells isolated from overweight and obese blood donors compared to normal weight donors. Flow cytometric analysis showed an altered expression pattern of activating and inhibitory NK cell receptors and adhesion molecules on NK cells of obese and overweight individuals compared to the normal weight control group.

Conclusion:

The decreased cytotoxic activity against tumor cells and the altered receptor expression pattern of NK cells from obese and overweight individuals indicate that the linkage of obesity and the known increased risk for breast and colorectal cancer can be related to an impaired NK cell functionality.