A Central Role for Death Receptor-Mediated Apoptosis in the Rejection of Tumors by NK Cells

Abstract

NK cells provide a line of defense against tumors and virus-infected cells that have lost the expression of one or more MHC class I isoforms. Here, we investigate whether inhibitors of apoptosis can block the rejection of tumors mediated by NK cells, by introducing the long form of Fas-associated death domain-like IL-1β-converting enzyme-associated inhibitory protein (FLIPL) and poxvirus cytokine response modifier A (CrmA) into the MHC class I-deficient T lymphoma cell line RMA-S. RMA-S cells do not normally express Fas in vitro, and it was previously postulated that the rejection of these tumors by NK cells is strictly perforin dependent. We show that perforin-deficient NK cells directly mediate Fas up-regulation on RMA-S cells and thereafter kill the cells in a Fas-dependent manner, and that RMA-S FLIPL and RMA-S CrmA are protected from such killing. When injected in immunocompetent recipients, RMA-S cells up-regulate Fas, rendering in vivo-passed mock-transduced cells sensitive to Fas-mediated apoptosis. Moreover, RMA-S FLIPL and RMA-S CrmA cells establish aggressive tumors, in contrast to RMA-S mock cells that are rejected. These results demonstrate that FLIPL and CrmA function as tumor progression factors by protecting MHC class I-deficient tumors from rejection mediated by NK cells. Moreover, our data indicate that death receptor-mediated apoptosis has a more prominent role in the clearance of NK-sensitive tumors than previously suggested.

Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-Human Immunodeficiency Virus Activity

“…The findings that (i) NK cells can mediate cytotoxicity by TRAIL (7,32,35,54,63,65,77), (ii) that IL-15 potentiates NK cell cytolytic activity, and (iii) that TRAIL has intrinsic activity against a variety of virally infected targets (5,11,14,17,21,34,41,45,46,73,76) suggest a role for IL-15 to potentiate TRAIL-mediated NK cell viricidal activity. We demonstrate that PBL and resting memory cells from infected individuals express high levels of the TRAIL death receptors and undergo cell death following TRAIL treatments (29,33,45), suggesting that these cells are potential targets for TRAIL killing.…”

Live and let die: regulatory mechanisms in Fas-mediated apoptosis

“…Increased resistance to Fas-mediated apoptosis by MMP-7 may also play a role in tumour progression. [134]. Cytotoxic T lymphocytes (CTL) can also promote transcription of Fas receptor in target cells through an interferon-γ (IFN-γ)-dependent mechanism [135].…”

Immunobiology of the TAM receptors

“…The effectors of this arm of the innate response are NK cells 63 , and the TAM signalling system also has an important role in regulating the activity of these cells 22 . This regulation again appears to be carried out in concert with cytokine receptors.On activation, NK cells kill their target cells through the exocytosis of perforin-and granzyme-containing granules, and the secretion of CD95 ligand and TNF-related apoptosisinducing ligand (TRAIL) [64][65][66][67][68] . NK cells also produce a variety of cytokines, including IFNγ, TNF and granulocyte/macrophage colony-stimulating factor (GM-CSF) [69][70][71] .…”