CMV Replication Drives IFNγ-Mediated Sensitization of AML Cells to Cytotoxic Killing Through the NKG2C-HLA-E Axis

Human cytomegalovirus (CMV) infection represents a significant risk factor for transplant recipients, including patients undergoing hematopoietic stem cell transplantation (HSCT). Interestingly, several studies have reported an association between early CMV reactivation and a reduced risk of leukemia relapse, particularly in acute myeloid leukemia (AML). Given that CMV profoundly shapes the natural killer (NK) cell compartment, a contribution of CMV-primed NK cells to this effect has been proposed.

To explore this mechanism, we analyzed the relationship between NK cell functionality and CMV reactivation in the context of AML. Consistent with observations in peripheral blood, CMV-seropositive HSCT recipients displayed expanded NKG2C ^pos NK cell populations within the bone marrow, characterized by high Granzyme B expression. CMV replication was associated with elevated plasma IFNγ levels, which in vitro rendered AML cells more susceptible to apoptosis when co-cultured with peripheral blood mononuclear cells. Importantly, IFNγ treatment modulated NK cell responses by inducing a variety of NK cell ligands including HLA-E on primary bone marrow-derived blasts and AML cell lines. In line with this, the activation of CMV-associated NKG2C ^pos NK cells was enhanced upon stimulation with IFNγ-pretreated AML cells.

In summary, our findings demonstrate that CMV replication induces a transient increase in IFNγ levels that influences both AML and NK cells, ultimately enhancing AML cell susceptibility to NK cell-mediated cytotoxicity initiated through the NKG2C-HLA-E axis.