Cancer immunology, immunotherapy : CIIJul 22, 2016

Glioblastoma cells resist killing and keep releasing inflammatory signals despite lower immune activation after attack by natural killer cells

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 6, 2026

Abstract

Natural killer (NK) cells showed decreased ability to kill brain cancer stem-like cells, leading to potential tumor growth inadequacy.

Brain cancer stem-like cells and poorly differentiated glioblastoma multiforme showed increased resistance to NK cell lysis when differentiated by split anergized NK supernatants.
Differentiation of these cells was associated with higher expression of CD54, B7H1, and MHC-I.
The resistance to NK cells and the differentiation of brain cancer stem-like cells were mediated by interferon (IFN)-γ and tumor necrosis factor (TNF)-α.
These brain cancer cells expressed low levels of tumor necrosis factor receptors and IFN-γ receptors.
Increased secretion of interleukin (IL)-6 and chemokine IL-8 was observed in the presence of decreased IFN-γ secretion during NK cell interaction.
NK-induced differentiation of brain cancer stem-like cells was independent of the functions of IL-6 and IL-8.

Simplified

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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Glioblastoma cells resist killing and keep releasing inflammatory signals despite lower immune activation after attack by natural killer cells

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