title: 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.
abstract: Natural killer (NK) cells are functionally suppressed in the glioblastoma multiforme (GBM) tumor microenvironment. We have recently shown that survival and differentiation of cancer stem-like cells (CSCs)/poorly differentiated tumors are controlled through two distinct phenotypes of cytotoxic and non-cytotoxic/split anergized NK cells, respectively. In this paper, we studied the function of NK cells against brain CSCs/poorly differentiated GBM and their NK cell-differentiated counterparts. Brain CSCs/poorly differentiated GBM, differentiated by split anergized NK supernatants (supernatants from NK cells treated with IL-2 + anti-CD16mAb) expressed higher levels of CD54, B7H1 and MHC-I and were killed less by the NK cells, whereas their CSCs/poorly differentiated counterparts were highly susceptible to NK cell lysis. Resistance to NK cells and differentiation of brain CSCs/poorly differentiated GBM by split anergized NK cells were mediated by interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Brain CSCs/poorly differentiated GBM expressed low levels of TNFRs and IFN-γRs, and when differentiated and cultured with IL-2-treated NK cells, they induced increased secretion of pro-inflammatory cytokine interleukin (IL)-6 and chemokine IL-8 in the presence of decreased IFN-γ secretion. NK-induced differentiation of brain CSCs/poorly differentiated GBM cells was independent of the function of IL-6 and/or IL-8. The inability of NK cells to lyse GBM tumors and the presence of a sustained release of pro-inflammatory cytokines IL-6 and chemokine IL-8 in the presence of a decreased IFN-γ secretion may lead to the inadequacy of NK cells to differentiate GBM CSCs/poorly differentiated tumors, thus failing to control tumor growth.
authors.affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA.|Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kozlowska
authors.affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA.
authors.forename: Han-Ching
authors.initials: HC
authors.lastname: Tseng
authors.affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA.
authors.forename: Kawaljit
authors.initials: K
authors.lastname: Kaur
authors.affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA.
authors.forename: Paytsar
authors.initials: P
authors.lastname: Topchyan
authors.affiliation: Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.|Department of Cell Biology, University of Miami, Miami, FL, USA.
authors.forename: Akihito
authors.initials: A
authors.lastname: Inagaki
authors.affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA.
authors.forename: Vickie T
authors.initials: VT
authors.lastname: Bui
authors.affiliation: Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.|Department of Cell Biology, University of Miami, Miami, FL, USA.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kasahara
authors.affiliation: The Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.|Department of Radiation Oncology, Division of Molecular and Cellular Oncology, UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Cacalano
authors.affiliation: Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA. ajewett@ucla.edu.|The Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. ajewett@ucla.edu.|UCLA School of Dentistry, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA. ajewett@ucla.edu.
authors.forename: Anahid
authors.initials: A
authors.lastname: Jewett
mesh_terms: D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005909:Glioblastoma / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000172:deficiency / Q000276:immunology*; D007376:Interleukin-2 / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology*; D016209:Interleukin-8 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D007376:Interleukin-2; D015850:Interleukin-6; D016209:Interleukin-8; D007371:Interferon-gamma
keywords: Brain cancer stem cells; GBM; IFN-γ; Immunotherapy; NK cells