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2016 ; 5
(8
): e1196308
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Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them
resistant to NK cell killing
#MMPMID27622064
Kearney CJ
; Ramsbottom KM
; Voskoboinik I
; Darcy PK
; Oliaro J
Oncoimmunology
2016[Aug]; 5
(8
): e1196308
PMID27622064
show ga
Acute myeloid leukemia (AML) is associated with poor natural killer (NK) cell
function through aberrant expression of NK-cell-activating receptors and their
ligands on tumor cells. These alterations are thought to promote formation of
inhibitory NK-target cell synapses, in which killer cell degranulation is
attenuated. Allogeneic stem cell transplantation can be effective in treating
AML, through restoration of NK cell lytic activity. Similarly, agents that
augment NK-cell-activating signals within the immunological synapse may provide
some therapeutic benefit. However, the receptor-ligand interactions that
critically dictate NK cell function in AML remain undefined. Here, we demonstrate
that CD112/CD155 expression is required for DNAM-1-dependent killing of AML
cells. Indeed, the low, or absent, expression of CD112/CD155 on multiple AML cell
lines resulted in failure to stimulate optimal NK cell function. Importantly,
isolated clones with low CD112/155 expression were resistant to NK cell killing
while those expressing abundant levels of CD112/155 were highly susceptible.
Attenuated NK cell killing in the absence of CD112/CD155 originated from
decreased NK-target cell conjugation. Furthermore, we reveal by time-lapse
microscopy, a significant increase in NK cell 'failed killing' in the absence of
DNAM-1 ligands. Consequently, NK cells preferentially lysed ligand-expressing
cells within heterogeneous populations, driving clonal selection of
CD112/CD155-negative blasts upon NK cell attack. Taken together, we identify
reduced CD155 expression as a major NK cell escape mechanism in AML and an
opportunity for targeted immunotherapy.
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