Abstract
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 I, and mediated by the combination of membrane-bound or secreted IFN-γ and TNF-α 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 TNF-α and IFN-γ 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-γ antibody in the absence of anti-TNF-α 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 LFA-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 IL-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.
Highlights
Recent advances in our understanding of anti-tumor immune responses and cancer biology have revealed a complex dynamic interaction between the immune effectors and the tumor cells
RESISTANCE OF DIFFERENTIATED oral squamous carcinoma cells (OSCCs) BUT NOT STEM-LIKE oral squamous cancer stem cell (OSCSC) AND Dental pulp stem cells (DPSCs) TO NK CELL-MEDIATED CYTOTOXICITY; LOSS OF NK CELL CYTOTOXICITY AND GAIN IN SECRETION OF IFN-γ AFTER NK CELL RECEPTOR SIGNALING NK cells were left untreated or treated with anti-CD16 antibody and/or IL-2 for 18–24 h before they were used with OSCSCs or their differentiated counterparts OSCCs
We had previously characterized stem-like OSCSCs and differentiated OSCCs based on their surface expression [29], and in this report we extended the characterization of stem-like OSCSCs to include other stem cell markers of CD26, CD326 (EpCam), CD166, and CD338 (Figures 1B,C)
Summary
Recent advances in our understanding of anti-tumor immune responses and cancer biology have revealed a complex dynamic interaction between the immune effectors and the tumor cells. Effectors of the immune system are known to shape tumor cells (immuno-editing) and select for cancers with reduced immunogenicity and enhanced capacity to actively induce immunosuppression. The same effector mechanisms are likely responsible for the selection of healthy stem cells with enhanced capacity to induce immunosuppression for the ultimate goal of wound healing, tissue regeneration, and cessation of inflammation. Many factors responsible for the suppression of NK cell cytotoxicity in humans have been previously identified [1,2,3,4,5,6]. NK cell cytotoxicity is suppressed after their interaction with stem cells [15,16,17]
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