Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing

Abstract

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 ligandexpressing 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.

PD-L1 and IAPs co-operate to protect tumors from cytotoxic lymphocyte-derived TNF

“…This type of treatment is likely to be effective against hematological tumors, which are characterized by suppressed NK cell effector function prior to chemotherapy or allogeneic stem cell plantation. 46,47 NK cells can also lyse tumor cells through the TRAIL/Fas pathway, independently of perforin. Because it is known that SMs can greatly sensitize tumor cells to death mediated by TRAIL or Fas ligand, 48 antagonizing IAPs may improve this pathway in tumors that express DR4/5 or CD95.…”

The number of CD56dim NK cells in the graft has a major impact on risk of disease relapse following allo-HSCT

“…CD112 and CD155 are the 2 ligands of DNAM and are expressed by AML blast cells. 32 Moreover, DNAM-dependent killing of AML cell lines has been shown in vitro, 33 and decreased expression of DNAM has been demonstrated on NK cells taken from patients with AML and is believed to act as a mechanism of tumor evasion. 34 Interestingly, the expression of DNAM was increased on CD56 dim NK cells in CMV seropositive donors (supplemental Figure 6) and may potentially contribute toward the association between CMV reactivation following allo-HSCT and protection from relapse.…”

CD226 deficiency improves cognitive functions and ameliorates anxiety‐like behaviors in mice

“…Neural CAMs comprise the cadherin, integrin, and immunoglobulin superfamily (IgSF) that have been demonstrated to be involved in target-cell recognition, neuronal cell migration, formation of complex glial networks, axon-bundle formation, and activity-dependent plasticity of synapses, which surround axons and synapses (Redies & Takeichi, 1996). CD226, an adhesion molecule belonging to the immunoglobulin superfamily, has well-established roles in lymphocyte signaling, intercellular adhesion, cytotoxicity induced by T lymphocytes and NK cells, and cytokine secretion (Ayano et al, 2015;Gilfillan et al, 2008;Iguchi-Manaka et al, 2008;Kearney, Ramsbottom, Voskoboinik, Darcy, & Oliaro, 2016). Previous studies examining the role of CD226 have primarily focused on the function of immune cells.…”