From bench to bedside: Exploiting memory NK cell responses to leukemia

Natural killer (NK) cells belong to innate lymphoid immune cells that contribute to antitumor responses without requiring prior sensitization. There is strong evidence that NK cells may induce graft-vs-leukemia (GvL) effect without causing graft-vs-host disease (GvHD), and significant efforts are currently undertaken to design and optimize NK cell-based immunotherapeutic strategies against human cancers, particularly against leukemias. However, the results of a number of adoptive NK cell transfer studies have been somewhat disappointing. This may be explained with difficulties in integrating the sequentially appearing activating signals into a directed NK cell response and may also be due to the lack of longevity of the transferred NK cells. The recent understanding that NK cells share developmental and homeostatic properties with T cells led to the hypothesis that NK cells should be able to elicit an (antigen-specific) recall response and should as such theoretically confer the potential for self-renewal and clonal expansion which may translate into longevity. Although immunological memory is per se a hallmark of the adaptive immune system, recent studies performed in mice and humans indicate that NK cells may indeed acquire (under certain conditions) features of adaptive immune cells. This review pursues the aim of providing a general understanding of the cellular and molecular aspects of various forms of memory NK cells with inherent antitumor properties and attempt to describe the translation of this knowledge into recent clinical adoptive transfer protocols with the aim of optimally harnessing the memory NK cell response to certain leukemias.