CNU 87 Basic and Clinical Biological Sciences.
Affiliated with the Laboratory of Biochemistry, Molecular Biology and Nutrition - Pharmacy Department of the University of Clermont Auvergne.

One of the ECREIN team's research interests is the study of immunocompetent cells and their modulation by nutritional status in pathophysiological situations. Initially, our work on cell culture models (PBMCs) and animals (malnourished aged rats) demonstrated that aging is associated not only with a reduction in the number but also in the functionality of immune cells. This immunosenescence is responsible for an alteration in adaptive capacities to variations in nutritional intake (depletion and repletion of antioxidant vitamins and minerals, retinoic acid supplementation), and contributes to an increased risk of infection and the establishment of functional and metabolic dysregulations that promote the onset of chronic pathologies such as obesity and cancer.
Obesity and associated metabolic disorders are recognized risk factors for breast cancer and its recurrence, particularly during menopause. In the context of the dialogue between adipocytes and immunocompetent cells, tumor cells and immune cells, the increased neoplastic risk could be linked to a reduced anti-tumor vigilance exerted in particular by Natural Killer (NK) cells. Experimentally, in vitro, we demonstrated that despite a dose-dependent stimulation of the metabolic activity of Natural Killer cells (human NK-92 line), leptin at doses mimicking circulating levels in obesity, alters the cytotoxicity of NK cells differently depending on the cancer target. This effect results from a reduction in the expression of perforin and INF-g by NK cells co-cultured with MCF-7 cells and a stimulation of Trail expression by NK cells in the presence of MDA-MB231 cells. These effectors are respectively involved in cytotoxicity dependent on lytic granule exocytosis and that induced by ligands to death receptors.

Research Activities

In a first animal model, allowing the study of the in vivo impact of obesity on mammary development and the anti-tumor response of NK cells (BALB/C nu/nu mice, under high-fat diet, xenograft of MCF-7 human mammary cancer cells), we demonstrated that despite resistance to obesity, increased tumor growth is associated with a reduction in the number and activity of NK cells.

In a second experimental mouse model of overweight and syngeneic mammary cancer (aged C57BL/6 mice and E0771 cells), we demonstrated that carcinogenesis and tumor progression are associated with a change in the immune response favoring pro-tumor cells (myeloid derived suppressive cells (MDSC), tumor associated Type 2 macrophages (TAM2)) to the detriment of anti-tumor cells (NK cells, cytotoxic lymphocytes (LyTc), TAM1), which leads to greater tumor aggressiveness. In this same model, moderate physical activity induces a repolarization of the anti-tumor immune response via the recruitment of cytotoxic cells, thus limiting carcinogenesis.

Using the same model, we will study the impact of imposed physical activity on metabolic and biological parameters as well as on the tumor microenvironment. The objective will be to evaluate whether physical exercise at different intensity levels has a significant impact on the intra-tumor immune microenvironment in the first instance and in the second instance on the response to treatment.

Most notable publications

• Farges MC, Minet-Quinard R, Walrand S, Thivat E, Ribalta J, Winklhofer-Roob B, Rock E, Vasson MP. Immune status is more affected by age than by carotenoid depletion-repletion in healthy human subjects. Br J Nutr. 2012 Dec 14;108(11):2054-65.
• Lamas B, Goncalves-Mendes N, Nachat-Kappes R, Rossary A, Caldefie-Chezet F, Vasson MP, Farges MC. Leptin modulates dose-dependently the metabolic and cytolytic activities of NK-92 cells. J Cell Physiol. 2013 Jun;228(6):1202-9.
• Lamas B, Vergnaud-Gauduchon J, Goncalves-Mendes N, Perche O, Rossary A, Vasson MP, Farges MC. Altered functions of natural killer cells in response to L-Arginine availability. Cell Immunol. 2012 Dec;280(2):182-90.
• Vasson MP, Farges MC, Goncalves-Mendes N, Talvas J, Ribalta J, Winklhofer-Roob B, Rock E, Rossary A. Does aging affect the immune status? A comparative analysis in 300 healthy volunteers from France, Austria and Spain. Immun Ageing. 2013 Sep 6;10(1):38
• Lamas B, Nachat-Kappes R, Goncalves-Mendes N, Mishellany F, Rossary A, Vasson  MP, Farges MC. Dietary fat without body weight gain increases in vivo MCF-7 human breast cancer cell growth and decreases natural killer cell cytotoxicity. Mol Carcinog. 2015 Jan;54(1):58-71.

Other links

ECREIN

https://www.linkedin.com/in/marie-chantal-farges-490b72254/