1Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Korea.
2Department of Microbiology, University of Ulsan College of Medicine, Seoul, Korea.
Natural killer (NK) cells are innate lymphoid cells that are endowed with an intrinsic ability to kill tumor cells without the expense of prior activation. With an array of germ line-encoded receptors that recognize specific ligands on target cells, they sense and selectively kill tumor cells and thus play a pivotal role in the first line of defense against the development of cancer . Owing to such an innate selectivity against tumor cells, NK cells have gained considerable attention as promising therapeutic measures for cancer immunotherapy . Moreover, NK cell functions are often impaired in a variety of cancer patients, and the extent of NK cell dysfunction correlates with clinical prognosis. Thus, NK cells can be used as useful prognostic biomarkers. NK cell decision to kill target cells is determined by a subtle balance of signals transmitted from diverse activating and inhibitory receptors . NK cell activation is tightly controlled by the requirement for the engagement of multiple activating receptors upon encounter with target cells. Except for CD16 that mediates antibody-dependent cellular cytotoxicity (ADCC), neither single activating receptor is sufficient but requires co-engagement of specific pairs of activating receptors to trigger cytotoxicity of freshly isolated NK cells. For example, 2B4 requires combination with NKG2D or with DNAM-1 for synergistic activation of NK cells. Cytokines such as IL-2 or IL-15 lower the threshold for NK cell activation such that cytokine-stimulated NK cells can respond to single activating receptors for triggering of killing activity . In addition, inhibitory receptors such as KIRs and CD94-NKG2A, specific for MHC class I, dominantly antagonize such activation and thereby provide protection of healthy cells from killing by NK cells. The down-regulation of MHC class I for inhibitory receptor and/or up-regulation of specific ligands for activating receptor (e.g. NKG2D) are frequently observed on transformed/malignant cells, thus cooperatively allowing their effective destruction by NK cells . In this respect, many efforts have been made to enhance the therapeutic benefit of NK cells for cancer immunotherapy by manipulating NK cell effector function. Here, we describe recent advances in NK cell-based cancer immunotherapy with focus on NK cell activation and discuss its future perspectives.
Autologous NK cell deficiency is a well-known feature observed in many cancer patients, especially in patients with hematological malignancies. The several mechanisms suggested include up-regulation of inhibitory receptors on NK cells and down-regulation of the ligands on tumor cells for NK cell activating receptors . Thus, infusion of NK cells without this deficiency holds promise in the treatment of cancer. The initial studies of NK cell immunotherapy focused on adoptive transfer of
NK cells do not require recognition of specific antigen on tumor MHC to mediate killing activity. Instead, NK cells have a multiplicity of activating receptors with different ligand specificity and signaling properties: receptors associated with ITAM-bearing molecules (e.g., CD16, NKp30), DAP10-associated receptor NKG2D, receptors of the SLAM family (e.g., 2B4), and other receptors (e.g., DNAM-1) . Given the complexity and heterogeneity of activating ligand expression on tumor cells, it would be promising to target and modulate signaling molecules that limit NK cell activation and are common to multiple NK activating receptors. We recently reported the identification of signaling molecules in this category such as c-Cbl and GSK-3β (Fig. 1) . Certain tumors including acute lymphoblastic leukemia (ALL) have been characterized by the paucity of activating ligand expression for NK cell activation and thus are resistant to NK cell-mediated killing. In such a situation,
Despite significant progress made in the role of NK cells as a key sentinel in tumor surveillance, the mechanisms that control NK cell responses remain elusive. Accordingly, current efforts for NK cell based therapy have largely relied on the strategies that manipulate inhibitory receptor function using allogeneic NK cells and KIR-blocking antibody. Recent advances in understanding the mechanisms of NK cell activation, including those mediated by diverse activating receptors, provide new therapeutic options to enhance NK cell reactivity against cancer. In this regard, strategies that augment sensitization of tumor cells to NK cell-mediated killing such as up-regulation of the activating ligands on tumor cells and modulation of immunosuppressive tumor microenvironment have also been pursued (Fig. 1) . Furthermore, several reliable protocols for GMP-grade NK cell expansion in large scale
Strategies aiming at enhancing natural killer (NK) cell reactivity against cancer. Several strategies have been developed to restore or enhance tumor eradication by NK cells: blockade of inhibition, enhancement of activation, or augmentation of tumor susceptibility. These strategies may be combined in a cooperative way to optimize NK cell-based cancer immunotherapy depending on the context.