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

Han-Ching Tseng,Armin Behel,Jackelyn A Alva,Aida Arasteh,No-Hee Park,Wendy Yang,Gina Walter,Anahid Jewett,Christian Head,Nicholas Cacalano,Antonia Teruel,Harvey R Herschman,April D Pyle,Avina Paranjpe,Tomo-O Ishikawa

doi:10.1371/journal.pone.0011590

Han-Ching Tseng, Armin Behel + Show 13 more

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https://doi.org/10.1371/journal.pone.0011590

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Journal: PLoS ONE	Publication Date: Jul 16, 2010
Citations: 141	License type: CC BY 4.0

Affiliation: University of California, Los Angeles, Broad Center

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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.

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Immunosuppression and tumor escape from immune recognition are thought to be the two major factors responsible for the establishment and progression of cancer
We screened a number of different primary oral squamous cell carcinomas (OSCC) derived from patients at University of California Los Angeles (UCLA), and selected pg/ml (MFI*)
HEp2-vec, HEp2-IkB(S32AS36A), UCLA-OSCCs, and UCLA-OSCSCs were cultured at 16105 cells/ml and the constitutive levels of secreted Granulocyte Monocyte-Colony Stimulating Factor (GM-CSF), IL-6, and IL-8 were determined using multiplex ELISA array kit

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Introduction

Immunosuppression and tumor escape from immune recognition are thought to be the two major factors responsible for the establishment and progression of cancer. A number of factors responsible for the suppression of NK cell cytotoxicity in humans have been identified previously [1,2,3,4,5,6]. The significance and the precise mechanism of NK suppression induced during their interaction with either tumor cells or healthy primary cells are not well understood. NK cell cytotoxicity is suppressed after their interaction with stem cells [11,12,13]. In contrast the interaction of NK cells with the resistant tumors does not lead to suppression of NK cell cytotoxicity [14]. Many mechanisms have been proposed for the functional inactivation of tumor associated NK cells including the over-expression of Fas ligand, the loss of mRNA for granzyme B [2] and decreased CD16 and its associated zeta chain [15]

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