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Another series of studies analyzed the interaction between chronic alcohol consumption and immune-system functioning in female C57BL/6 mice implanted with B16BL6 melanoma cells under the skin (i.e., subcutaneously). In these studies, the animals continuously received 20 percent w/v ethanol in the drinking water and generally were inoculated with B16BL6 melanoma after 12 weeks or longer of this treatment. The analyses found that in the alcohol-exposed, melanoma-bearing animals the overall numbers of peripheral blood lymphocytes (which include various types of immune cells) were lower than in water-drinking controls when determined 11, 14, and 17 days after tumor inoculation (Zhang et al. 2012). This was in contrast to normal mice not injected with melanoma cells, in which the number of lymphocytes was not altered by alcohol. The decrease in cells was not caused by cell death (i.e., apoptosis). Additional analyses demonstrated that the lowered lymphocyte numbers (i.e., lymphopenia) were associated with a two- to fourfold decrease in mature B cells as well as in CD4+ and CD8+ T cells. Further examination demonstrated that the decrease in mature B cells in the blood was associated with impaired B-cell circulation resulting from a down regulation in the formation of compound called sphingosine-1-phosphate and its receptors. Formation of sphingosine-1-phosphate is mediated (i.e., catalyzed) by an enzyme called sphingosine kinase 1, which is an important regulator of tumor progression in melanoma and several other cancers (Meng et al. 2014). This enzyme and other components of the sphingosine-1-phosphate pathway currently are being examined as potential targets for cancer drug development (Pyne and Pyne 2013; Tabasinezhad et al. 2013). Zhang and colleagues (2012) concluded that the severe decrease in mature B cells in the blood of the alcohol-exposed and tumor-inoculated animals could result from inhibition of B-cell migration from the spleen to the blood resulting from impairment of the sphingosine-1-phosphate signaling pathway. The importance and role of mature B cells in antitumor immune responses is still unclear. They play a dual role by both inhibiting (Inoue et al. 2006) and facilitating antitumor immune response through production of cytokines and enhancement of T-cell activation (DiLillo et al. 2010). Thus, impaired circulation of B cells attributed to alcohol consumption (Zhang et al. 2012) could negatively affect T-cell function.
The percentage and number of CD3+NK1.1+ invariant NKT cells was elevated in the blood of alcohol-consuming, B16BL6 melanoma-bearing mice especially at day 14 after tumor inoculation (Zhang et al. 2012). These cells have important regulatory functions and can either promote antitumor immune responses or inhibit them. Initially, these cells express a cytokine profile that favors antitumor immune responses (i.e., a high ratio of IFN-γ to IL-4). After repeated activation, however, these cells become anergic and switch to a cytokine profile that inhibits anti-tumor immune responses and favors tumor progression (i.e., a high ratio of IL-4 to IFN-γ) (Parekh et al. 2005). The invariant NKT cells from the alcohol-consuming, melanoma-bearing mice exhibit a high IL4/IFN-γ ratio, indicating that they express a cytokine profile favoring immune inhibition and tumor progression (Zhang et al. 2015). 2b1af7f3a8