Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing.
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.
Immune Defense Laboratory, Cancer Immunology Division, The Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
Conor J
CJ
Kearney
Immune Defense Laboratory, Cancer Immunology Division, The Peter MacCallum Cancer Center , East Melbourne, Victoria, Australia.
Kelly M
KM
Ramsbottom
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia; Killer Cell Biology Laboratory, Cancer Immunology Division, The Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia.
Ilia
I
Voskoboinik
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia; Immunotherapy Laboratory, Cancer Immunology Division, The Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia.
Phillip K
PK
Darcy
Immune Defense Laboratory, Cancer Immunology Division, The Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
Jane
J
Oliaro
AML; CD155; DNAM-1; cancer; immunological synapse; immunotherapy; lymphocytes