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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

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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.

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Abbreviations

B7H1:

B7 homolog 1

CSCs:

Cancer stem-like cells

GBM:

Glioblastoma multiforme

hr:

Human recombinant

IFN-γR:

Interferon-γ receptor

KLRG1:

Killer cell lectin-like receptor subfamily G member 1

LIF:

Leukemia inhibitory factor

MHC:

Major histocompatibility complex

MICA:

MHC class I polypeptide-related sequence A

NK:

Natural killer

OSCSCs:

Oral squamous carcinoma stem cells

TNFR:

Tumor necrosis factor receptor

ULBP:

UL16-binding protein

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Acknowledgments

This study was Funded by Faculty Grants Program (FGP) and UCLA School of Dentistry seed grants. Anna K. Kozlowska was supported by the Polish Ministry of Sciences and Higher Education and Mobility Plus award.

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Author notes

  1. Akihito Inagaki & Noriyuki Kasahara

    Present address: Department of Cell Biology, University of Miami, Miami, FL, USA

Authors and Affiliations

  1. Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA

    Anna K. Kozlowska, Han-Ching Tseng, Kawaljit Kaur, Paytsar Topchyan, Vickie T. Bui & Anahid Jewett

  2. Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland

    Anna K. Kozlowska

  3. Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

    Akihito Inagaki & Noriyuki Kasahara

  4. The Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA

    Nicholas Cacalano & Anahid Jewett

  5. Department of Radiation Oncology, Division of Molecular and Cellular Oncology, UCLA School of Medicine, Los Angeles, CA, USA

    Nicholas Cacalano

  6. UCLA School of Dentistry, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA

    Anahid Jewett

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  1. Anna K. Kozlowska
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Kozlowska, A.K., Tseng, HC., Kaur, K. et al. 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. Cancer Immunol Immunother 65, 1085–1097 (2016). https://doi.org/10.1007/s00262-016-1866-x

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