Besides their innate ability to rapidly produce effector cytokines and kill virus-infected or transformed cells, natural killer (NK) cells display a strong capability to adapt to environmental modifications. In this context, cytomegalovirus (CMV) infection drives an epigenetically-shaped, long-living, hyperfunctional NK subpopulation dubbed adaptive or memory NK cells which are endowed with an enhanced ability to mediate CD16-dependent cytotoxicity and IFN-gamma production. In humans, memory NK cells are commonly defined by either a lack of the signaling adaptor chain FcepsilonRIgamma and/or a gain of the activating receptor NKG2C, along with increased levels of CD57 maturation marker. Although the frequencies of FcepsilonRIgamma- and NKG2C+ NK cells positively correlate, such phenotypic markers are often dissociated, thus evidencing a remarkable degree of heterogeneity within memory NK cell population.
In a large cohort of healthy CMV seropositive individuals we want to characterize memory NK cell subpopulations by evaluating their frequency and absolute number, the molecular and metabolic signature relevant for their survival and/or self-renewal advantage, as well as the capability to mediated antibody (Ab)-dependent effector functions and to proliferate in response to CD16 stimulation.
The expected results of this project will allow to better define the phenotypic and functional heterogeneity of memory NK cells. We believe that the findings will uncover previously unrecognized mechanisms of NK cell plasticity and provide information with a strong translational potential. Indeed, the long-term survival, the resistance to tumor-dependent immunosuppressive microenvironment, the amplified functional responses to IgG-opsonized tumor cells, and in vitro expansion capability, make memory NK cells an attractive candidate for adoptive transfer-based immunotherapeutic strategies (14).
In particular, CAR-NK cell therapies, already in clinical trials (15), hold promise in term of safety and toxicity respect to CAR-T cells and are considered as potential universal cell therapy off-the-shelf products. In the optimization of CAR-NK cell therapies, the exploitation of memory NK cells may have a considerable potential.
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