Induction of split anergy conditions natural killer cells to promote differentiation of stem cells tnrough cell-cell contact and secreted factors

In this paper, we provide evidence that anergized NK cells through secreted factors and direct cell cell contact have the ability to induce differentiation of healthy dental pulp stem cells and stem cell of apical papillae as well as transformed oral squamous cancer stem cell (OSCSC) and Mia-Paca-2, poorly differentiated stem-like pancreatic tumors, resulting in their resistance to NK cell-mediated cytotoxicity. Induction of NK cell resistance and differentiation in the stem cells correlated with the increased expression of CD54, B7H1, and MHC class 1, and mediated by the combination of membrane-bound or secreted IFN-gamma and INF-alpha from the NK cells since antibodies to both cytokines and not each one alone were able to inhibit differentiation or resistance to NK cells. Similarly, antibodies to both INF-alpha and IFN-gamma d were required to prevent NK-mediated inhibition of cell growth, and restored the numbers of the stem cells to the levels obtained when stem cells were cultured in the absence of anergized NK cells. Interestingly, the effect of anti-IFN-gamma antibody in the absence of anti-INF-alpha antibody was more dominant for the prevention of increase in surface receptor expression since its addition abrogated the increase in CD54, B7H1, and MHC class I surface expression. Antibodies to CD54 or LEA-1 was unable to inhibit differentiation whereas antibodies to MHC class I but not B7H1 increased cytotoxicity of well-differentiated oral squamous carcinoma cells as well as OSCSCs differentiated by the 11,2 + anti-CD16 mAb-treated NK cells whereas it inhibited the cytotoxicity of NK cells against OSCSCs. Thus, NK cells may inhibit the progression of cancer by killing and/or differentiation of cancer stem cells, which severely halt cancer growth, invasion, and metastasis.