Tumor Microenvironment may Shape the Function and Phenotype of NK Cells Through the Induction of Split Anergy and Generation of Regulatory NK Cells

Abstract

Cytotoxic function of NK cells is suppressed in the tumor microenvironment by a number of distinct effectors. Furthermore, decreased peripheral blood NK cell cytotoxicity has been documented in cancer patients. We have previously demonstrated evidence for the role of NK cells in specific elimination of stem cells and not their differentiated counterparts. In this regard, NK cells were found to 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), human mesenchymal stem cells (hMSCs), human dental pulp stem cells (hDPSCs) and induced human 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. There is also a stage wise susceptibility to NK cell mediated cytotoxicity in pancreatic tumors in which case the poorly differentiated tumors are lysed much more than their moderately differentiated tumors. The well differentiated pancreatic tumors were lysed the least when compared to either the moderately differentiated tumors or to poorly differentiated tumors. We have also reported that inhibition of differentiation or reversion of cells to a less-differentiated stage by blocking NF-jB or gene deletion of COX2 significantly augmented NK cell cytotoxicity against both transformed and healthy cells. Therefore, we propose that the two stages of NK cell maturation namely CD16 ? CD56 dim CD69-NK cells are important for the selection of stem

Differentiation by NK cells is a prerequisite for effective targeting of cancer stem cells/poorly differentiated tumors by chemopreventive and chemotherapeutic drugs

“…Based on these results, we have proposed, that NK cells play a significant role in differentiation of cells by providing critical signals via secreted cytokines as well as direct cell-cell contact 18. In addition, we have demonstrated that human monocytes promote significant split anergy in NK cells 16, 19, 21, 66-68. Induction of split anergy in NK cell effector function is thought to ultimately aid in driving differentiation of healthy, as well as transformed stem-like cells 19, 66-69.…”

Resistance to cytotoxicity and sustained release of interleukin-6 and interleukin-8 in the presence of decreased interferon-γ after differentiation of glioblastoma by human natural killer cells

“…The stage of differentiation of many tumors including GBM is predictive of their sensitivity to NK cell lysis since CSCs/poorly differentiated GBM tumors are targets of NK cells, whereas those differentiated with split anergized NK cell supernatants display resistance to NK cell-mediated cytotoxicity [32, 41–46]. We have shown that NK cells play a significant role in differentiation of tumors by providing critical signals via secreted IFN-γ and TNF-α, as well as direct cell–cell contact [10, 35].…”

“…We have shown that NK cells play a significant role in differentiation of tumors by providing critical signals via secreted IFN-γ and TNF-α, as well as direct cell–cell contact [10, 35]. Furthermore, tumor differentiation is likely supported by signals from other immune effectors, such as monocytes and macrophages within the tumor stroma to induce split anergy in NK cells [41, 43–46]. Interestingly, significantly higher amounts of NK supernatant containing IFN-γ were required to differentiate X02GB in comparison with OSCSCs resulting in tumor growth inhibition, upregulation of CD54, B7H1 and MHC-I expression and resistance to NK cell-mediated cytotoxicity.…”

Differential Cytotoxicity but Augmented IFN-γ Secretion by NK Cells after Interaction with Monocytes from Humans, and Those from Wild Type and Myeloid-Specific COX-2 Knockout Mice

“…Specifically, the deletion of NF-κB in tumors was found to increase NK cell-mediated cytotoxicity and secretion of IFN-γ significantly ( 2 , 3 ), and induce auto-immunity and inflammation in vivo ( 63 , 64 ). Moreover, conditional knockout of STAT3 in hematopoietic cells was found to result in the induction of colitis in mice due to chronic gut inflammation ( 57 , 65 ). Furthermore, we have shown previously that NK cells target poorly differentiated cells or stem cells with lower expression of many important differentiation receptors ( 45 , 60 , 66 ).…”