Abstract
The mechanism of suppression of NK cytotoxicity in cancer patients is not clearly established. In this paper we provide evidence that anergized NK cells induce differentiation of healthy Dental Pulp Stem Cells (DPSCs) or transformed Oral Squamous Cancer Stem Cells (OSCSCs) resulting in cell growth inhibition, resistance to NK cell-mediated cytotoxicity and prevention of inflammatory mediators secretion. Induction of cytotoxicity resistance in differentiated cells correlated with increased CD54 and MHC class I surface expression and mediated by the combination of IFN-γ and TNF-α since antibodies to both, but not each cytokine alone, was able to inhibit resistance. In contrast, inhibition of cytokine and chemokine release was mediated by IFN-γ since the addition of anti-IFN-γ antibody, and not anti-TNF-α, restored secretion of inflammatory mediators in NK cell cultures with differentiated DPSCs and OSCSCs. There was a gradual and time dependent decrease in MHC class I and CD54 expression which correlated with the restoration of NK cell cytotoxicity, augmentation of cytokine secretion and increased cell growth from days 0-12 post NK removal. Continuous presence of NK cells is required for the maintenance of cell differentiation since the removal of NK cell-mediated function reverses the phenotype and function of differentiated cells to their stem-like cells.
Highlights
Immune effectors such as Natural Killer cells and T cells are thought to shape tumor cells and select for cancers with reduced immunogenicity and enhanced capacity to induce immunosuppression [1]
To determine whether NK cells target cancer stem cells and not their differentiated counterparts, NK cells were left untreated or treated with anti-CD16 antibody and/or IL-2 for 18–24 hours to induce split anergy before they were used in cytotoxicity assays against Oral Squamous Cancer Stem Cells (OSCSCs) and OSCCs
Both untreated and IL-2 treated NK cells mediated higher lysis of OSCSCs when compared to OSCCs in 51Cr release assay (P < 0.05) (Supplementary Figure 1A) [27] and IL-2 treated NK cells secreted higher levels of IFN-γ in co-culture with OSCSCs when compared to OSCCs (P < 0.05) (Supplementary Figure 1B) [27]
Summary
Immune effectors such as Natural Killer cells and T cells are thought to shape tumor cells and select for cancers with reduced immunogenicity and enhanced capacity to induce immunosuppression [1] They are responsible for the selection of healthy stem cells with enhanced capacity to induce immunosuppression in order to mediate wound healing, tissue regeneration and cessation of inflammation. Such mechanisms are thought or speculated to be the underlying cause of immunosuppression in tumors no direct evidence, clear data or even physiological relevance has previously been offered to demonstrate the rationale for tumor mediated immunosuppression. Any intervention or strategy to eliminate tumors should consider both mechanisms since they are interrelated
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