Increased Lysis of Stem Cells but Not Their Differentiated Cells by Natural Killer Cells; De-Differentiation or Reprogramming Activates NK Cells

Abstract

The aims of this study are to demonstrate the increased lysis of stem cells but not their differentiated counterparts by the NK cells and to determine whether disturbance in cell differentiation is a cause for increased sensitivity to NK cell mediated cytotoxicity. Increased cytotoxicity and augmented secretion of IFN-γ were both observed when PBMCs or NK cells were co-incubated with primary UCLA oral squamous carcinoma stem cells (UCLA-OSCSCs) when compared to differentiated UCLA oral squamous carcinoma cells (UCLA-OSCCs). In addition, human embryonic stem cells (hESCs) were also lysed greatly by the NK cells. Moreover, NK cells were found to lyse human Mesenchymal Stem Cells (hMSCs), human dental pulp stem cells (hDPSCs) and human induced pluripotent stem cells (hiPSCs) significantly more than their differentiated counterparts or parental lines from which they were derived. It was also found that inhibition of differentiation or reversion of cells to a less-differentiated phenotype by blocking NFκB or targeted knock down of COX2 in monocytes significantly augmented NK cell cytotoxicity and secretion of IFN-γ. Taken together, these results suggest that stem cells are significant targets of the NK cell cytotoxicity. However, to support differentiation of a subset of tumor or healthy untransformed primary stem cells, NK cells may be required to lyse a number of stem cells and/or those which are either defective or incapable of full differentiation in order to lose their cytotoxic function and gain the ability to secrete cytokines (split anergy). Therefore, patients with cancer may benefit from repeated allogeneic NK cell transplantation for specific elimination of cancer stem cells.

Natural killer cells as effectors of selection and differentiation of stem cells: Role in resolution of inflammation

“…Because of their ability to drive differentiation, anergized NK cells may have the ability to halt inflammation since differentiated cells are no longer targeted by the NK cells and T-cells and they do not induce cytokine secretion by the NK and T-cells (Figure 4) (Jewett et al, 2010;Tseng et al, 2010). This function of NK cells is similar to T-regulatory cells since they are inhibitory and are capable of decreasing the magnitude of inflammation in a number of previous studies.…”

“…All different types of stem cells became resistant to NK cell-mediated cytotoxicity once they were differentiated (Table 3). In addition, higher sensitivity of hiPSC to NK cell mediated lysis was also observed when compared to the parental line from which they were derived (Jewett et al, 2010;Tseng et al, 2010) (Table 3). Differentiation of XO1-NS and XO2-NS also rendered them more resistant to NK cell mediated cytotoxicity (Table 3; manuscript submitted).…”

“…More importantly, OSCSC expressed CD133 and CD44 bright oral stem cell markers (Jewett et al, 2010;Tseng et al, 2010); in contrast, differentiated OSCC expressed lower levels of CD44 surface receptors.…”

Cell-based immunotherapy in stage IIIA inflammatory breast cancer with declining innate immunity following successive chemotherapies: A case report

“…This may be due to the effects of the infused NK cells on encountered cancer cell targets, including circulating tumor cells, as NK cells have been observed to lyse circulating tumour emboli efficiently (25). Starting NK cell-based AIET immediately after diagnosis, as in the present case, may be advantageous, as these NK cells may also act on breast cancer cells that migrate to the bone marrow during the early stages of the disease, as well as targeting treatment-resistant breast cancer stem cells (3,5,6). Therefore, an assessment of NK cell expansion potential and cytotoxicity following conventional therapies in several patients may elucidate the potential loopholes of the immune system through which cancer is able to evade these immune cells, leading to disease recurrence and resistance to treatment.…”

“…These migrated cancer cells remain dormant, becoming active later thereby causing recurrence or advancement of the disease. CD3 -CD56 + or CD16 + natural killer (NK) cells that possess the ability to identify and kill target cancer cells (4), particularly cancer stem cells (5,6) without prior sensitization makes them an important player in immunosurveillance and cancer defense in vivo. Therefore, NK cell-based immunotherapy may be a promising therapeutic strategy against cancer (4).…”