A multifaceted approach targeting NK cells for better treatment of cancer: focus on hematological malignancies.

Abstract

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 [1]. Owing to such an innate selectivity against tumor cells, NK cells have gained considerable attention as promising therapeutic measures for cancer immunotherapy [2,3]. 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 [1]. 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 [4]. 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 [5]. 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.