Expression of MHC I and NK ligands on human CD133+ glioma cells: possible targets of immunotherapy

Abstract

Mounting evidence suggests that gliomas are comprised of differentiated tumor cells and brain tumor stem cells (BTSCs). BTSCs account for a fraction of total tumor cells, yet are apparently the sole cells capable of tumor initiation and tumor renewal. BTSCs have been identified as the CD133-positive fraction of human glioma, whereas their CD133-negative daughter cells have limited proliferative ability and are not tumorogenic. It is well established that the bulk tumor mass escapes immune surveillance by multiple mechanisms, yet little is known about the immunogenicity of the CD133-positive fraction of the tumor mass. We investigated the immunogenicity of CD133-positive cells in two human astrocytoma and two glioblastoma multiforme samples. Flow cytometry analyses revealed that the majority of CD133-positive cells do not express detectable MHC I or natural killer (NK) cell activating ligands, which may render them resistant to adaptive and innate immune surveillance. Incubating CD133-positive cells in interferon gamma (INF-gamma) significantly increased the percentage of CD133-positive cells that expressed MHC I and NK cell ligands. Furthermore, pretreatment of CD133-positive cells with INF-gamma rendered them sensitive to NK cell-mediated lysis in vitro. There were no consistent differences in immunogenicity between the CD133-positive and CD133-negative cells in these experiments. We conclude that CD133-posistive and CD133-negative glioma cells may be similarly resistant to immune surveillance, but that INF-gamma may partially restore their immunogenicity and potentiate their lysis by NK cells.

Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells

“…The inhibition of NK cells is mediated by the inhibitory killer-cell immunoglobulin-like receptors or NKG2A/CD94 that recognize classical or nonclassical HLA class I molecules, respectively, which are often lost or reduced in malignant cells [13,14]. Contrarily to conventional chemotherapy, NK cells appear to recognize and kill undifferentiated stem-like cells [15,16] by virtue of their ability to target non-dividing cells and due to the low expression of MHC class I molecules and possible up-regulation of stress-induced activation ligands [17][18][19].…”

Cytotoxic activity of allogeneic natural killer cells on U251 glioma cells in vitro

“…Amplified NK cells possess 82.2±10.5% leukomonocytes (mean ± standard deviation) and the therapeutic effects of NK cells are enhanced by simultaneous venous injection with IFN-β. Clinical results demonstrate that autologous NK cells are safe and somewhat effective for the treatment of glioma (19)(20)(21)(22)(23). The present study indicates that allogeneic NK cells exhibit specific cytotoxic activity on glioma cells.…”

Running Head: Craniopharyngioma and Immune Response

“…Eisele et al [17], showed that human glioma cells express MICA/B as well as ULBP1-3 and that the expression of these ligands in glioma may be influenced by TGF-β. Moreover, Wu et al [18] Provided evidence that tumor-initiating cells within gliomas−also referred to as glioma stem cells and characterized by their CD133 cell surface marker expression−express NKG2D and NKp30/44/46 ligands. Our results show a perivascular infiltrate of CD20+ cells, and the following statistical differences when associating it with tumor size (p=0.004), histological type (p=0.013), brain infiltration and mode of inflammatory cell infiltration (p=0.000 respectively).…”