Tumor induced inactivation of natural killer cell cytotoxic function; implication in growth, expansion and differentiation of cancer stem cells

Abstract

Accumulated evidence indicates that cytotoxic function of immune effectors is largely suppressed in the tumor microenvironment by a number of distinct effectors and their secreted factors. The aims of this review are to provide a rationale and a potential mechanism for immunosuppression in cancer and to demonstrate the significance of such immunosuppression in cellular differentiation and progression of cancer. To that end, we have recently shown that NK cells mediate significant cytotoxicity against primary oral squamous carcinoma stem cells (OSCSCs) as compared to their more differentiated oral squamous carcinoma cells (OSCCs). In addition, human embryonic stem cells (hESCs), Mesenchymal Stem Cells (hMSCs), dental pulp stem cells (hDPSCs) and induced pluripotent stem cells (hiPSCs) were all significantly more susceptible to NK cell mediated cytotoxicity than their differentiated counterparts or parental cells from which they were derived. We have also reported that inhibition of differentiation or reversion of cells to a less-differentiated phenotype by blocking NFκB or targeted knock down of COX2 in primary monocytes in vivo significantly augmented NK cell function. Total population of monocytes and those depleted of CD16(+) subsets were able to substantially prevent NK cell mediated lysis of OSCSCs, MSCs and DPSCs. Taken together, our results suggest that stem cells are significant targets of the NK cell cytotoxicity. The concept of split anergy in NK cells and its contribution to tissue repair and regeneration and in tumor resistance and progression will be discussed in this review.

Keywords: NFκB; NK; apoptosis; cancer stem cells; differentiation.

Fig 1

Schematic representation of hypothetical model of oral cancer stem cell differentiation by NK cells. Based on our previous results , , OSCSCs initially express the phenotype listed in the figure (left panel). Upon conditioning of NK cells to lose cytotoxicity and gain in cytokine secretion and expressing CD16-CD56dim/-CD69+ surface phenotype (middle panel), either by immune inflammatory cells such as monocytes (for more detail see figure 2) or stem cells, the phenotype of stem cells is modified as shown in the right panel, and they become differentiated to support tissue regeneration.

Fig 2

Immune inflammatory cells are mainly concentrated in the connective tissue area right beneath the epithelial layer of OSCC. The slides from OSCC were prepared and stained with H&E (left panel). At the right panel the hypothetical model of NK cell conditioning in the tumor microenvironment is over imposed on the actual slide shown on the left panel. On the left panel significant infiltration of immune effectors right beneath the epithelial layer can be seen in the connective tissue area where the immune inflammatory cells are likely to condition NK cells to lose cytotoxicity and to support differentiation of epithelial cells. At the right panel two hypothetical mechanisms for conditioning of NK cells to support differentiation of stem cells are shown. In one scenario, NK cells, may first encounter and interact with either the other immune effectors as listed in the figure or the effectors of connective tissue such as fibroblasts to undergo split anergy (NK_SA). In a second scenario, NK cells may also directly encounter the stem cells at the base of the epithelial layer, in which case by eliminating their bound stem cells, they too can become anergized to support differentiation of other stem cells. Both mechanisms may be operational in the tumor microenvironment.