Natural Killer Cells Preferentially Target Cancer Stem Cells; Role of Monocytes in Protection Against NK Cell Mediated Lysis of Cancer Stem Cells

Abstract

Mounting effective anti-tumor immune responses by cytotoxic effectors is important for the clearance of tumors. However, accumulated evidence suggests that the 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 potential mechanism for immunosuppression in cancer, and to demonstrate the significance of such immunosuppression in cellular differentiation and tissue regeneration in pathological conditions, and progression of cancer. We have recently shown that increased NK cell function was seen when they were cultured with 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 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 augmented NK cell function significantly. 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. Therefore, patients with cancer may benefit from repeated allogeneic NK cell transplantation at the site of the tumor for specific elimination of cancer stem cells.

Malignant Pleural Effusion and ascites Induce Epithelial-Mesenchymal Transition and Cancer Stem-like Cell Properties via the Vascular Endothelial Growth Factor (VEGF)/Phosphatidylinositol 3-Kinase (PI3K)/Akt/Mechanistic Target of Rapamycin (mTOR) Pathway

“…One of these reports shows that tumor cells in the peritoneal cavity express PD-L1 and escape from CD8ϩ cytotoxic lymphocytes (40). Previously, studies reported that NK cells can recognize and kill tumor cells in an MHC-independent manner and that allogeneic NK cells preferentially target cancer stem cells (25,41). In this study, we found that cancer cells experienced EMT and acquired a CSC phenotype when exposed to malignant PE/ascites.…”

“…3E), two putative CSC markers, protecting cancer stem cells from chemotherapeutic agents (24). On the other hand, recent reports show that allogeneic NK cells preferentially target cancer stem cells (25). To test whether malignant PE/ascites influence the susceptibility to cytotoxicity of NK cells, we analyzed malignant PE/ascites-cultured tumor cells for their susceptibility to IL-2/IL-15-activated NK cell populations derived from healthy donors.…”

CTLA-4 Blockade Expands Infiltrating T Cells and Inhibits Cancer Cell Repopulation during the Intervals of Chemotherapy in Murine Mesothelioma

“…Hence, targeting stem cells may be of prime importance for long-term remission of the tumor. Immunotherapy may be a promising therapeutic option to target these cells and generate a long lasting memory response (47).…”

The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications

“…Emerging evidence suggests that host immune system has the ability to recognize CSCs and provoke an immune response. Early studies in HNSCC have shown that NK cells may preferably target CSCs (35). In addition, CSCs interact with tumor microenvironment.…”