The first report showing a protective effect of cytomegalovirus (CMV) against cancer relapse was published nearly 20 years ago, and this effect has been confirmed in several independent studies, including a large-scale clinical analysis of >2,500 patients with hematologic malignancies. While the protective effect of CMV is presumed to be due to a unique priming of the immune system, the mechanism of this priming is unknown. We are in a new era where the power of the immune response against cancer is just being realized. We have recently discovered oligoclonal expansions of highly differentiated NK cells expressing the activating receptor NKG2C in individuals having past infection with CMV. These NKG2C+ NK cells have an educated phenotype, as they are enriched for the expression of self HLA-C-specific inhibitory KIRs and appear to represent the human equivalent of “memory” or “adaptive” NK cells described in CMV-infected mice. Published work by our group has shown that these NKG2C+ NK cells display heightened effector functions, expand in transplant patients in response to reactivation of latent CMV and persist for at least one year post-transplant. They are transplantable from a CMV seropositive donor and expand in a seropositive recipient. We have extensive preliminary data showing that NKG2C is not the only marker for CMV-induced adaptive NK cells. We identified expansions of NK cells selectively lacking the proximal signaling molecules FcεR1γ, EAT-2 and SYK individually or in combination specifically in CMV seropositive blood donors and in transplant recipients that reactivated CMV. These cells are epigenetically primed for enhanced inflammatory cytokine production and survival and are functionally specialized for antibody-dependent cellular cytotoxicity (ADCC) through CD16. We will translate this research into methods to prime NK cells ex vivo or in vivo with potent function and prolonged in vivo survival for clinical use in patients with leukemia. We will test the hypothesis that the expansion of CMV- induced adaptive NK cells is associated with reduced cancer relapse by performing a high-resolution analysis of CMV-induced adaptive NK cells in our well-defined transplant cohorts and correlating this analysis with clinical outcomes. We will also test the hypothesis that STAT3 signaling and CD16 receptor engagement drives the expansion of adaptive NK cells both in vitro and using our bank of clinical samples. Finally, we will use our xenogeneic adoptive NK cell transfer model to test the anti-tumor effect of CMV-induced adaptive NK cells in vivo. The concept of CMV induced adaptive NK cells is new and little is know about these cells in humans. We have already discovered how to identify adaptive NK cell and we have clinical samples collected based on CMV reactivation. We are optimally positioned to definitively answer the question about whether adaptive NK cells can prevent relapse as our preliminary data suggests or...