ReviewNatural killer cell-mediated immunosurveillance of human cancer
Introduction
The concept of immunosurveillance of cancer was outlined half a century ago [1]. The general view was that tumor cell transformation is a frequent event and is under constant control by the immune system. A prediction of the concept was that genetically immunodeficient individuals, or those being treated with immunosuppressive drugs, would have a markedly increased incidence of cancer. At first, clinical observations provided only marginal support for this concept. The rate of spontaneous malignant transformation was likely overrated. However, based on data from experimental models in mice and epidemiological studies in humans [2], the concept has now gained acceptance in a wider research community. Indeed, patients with inherited or acquired immunodeficiencies, and patients on immunosuppressive drugs, have higher incidences of cancer [2]. Defects affecting T cells or other parts of the adaptive immune system have been particularly implicated in this context. However, innate constituents of the immune system, including natural killer (NK) cells, may also play a significantly important role.
NK cells were initially identified due to their ability to kill tumor cell lines in vitro [3], [4]. Since that discovery, a large number of studies has demonstrated NK cell-mediated killing of many types of tumor cell lines in vitro, and in experimental animal models [5], [6], [7]. Studies have also shown that NK cells are involved in rejection responses against experimentally induced and spontaneously developing tumors in mice [8], [9], [10]. Indirect evidence for NK cell targeting of human tumors has come from studies of allogeneic hematopoietic stem cell transplantation (HSCT), in particular haploidentical HSCT against acute myeloid leukemia (AML) [11], [12].
NK cell recognition of tumor cells is a tightly regulated process involving the interaction of specific ligands on the tumor cells with NK cell receptors and subsequent integration of signals derived from such receptors in the responding NK cells [13], [14]. The earliest insights into the molecular specificity of NK cells were based on the observation that NK cell cytotoxicity was triggered by tumor cells lacking expression of all (or certain) self-major histocompatibility complex (MHC) class I molecules, a phenomenon referred to as “missing-self” recognition [6], [15]. These observations led to the identification of specific NK cell-inhibitory receptors that recognize MHC class I molecules [16], [17] and were later followed by identification of NK cell-activating receptors, binding specific ligands expressed by tumor cells [18], [19], [20], [21], [22], [23].
Furthermore, in contrast to what was initially thought, it is now clear that NK cells are not a homogeneous set of cytotoxic lymphocytes. Rather, during the past two decades we have gained a deep understanding of this population of lymphocytes revealing significant insights into their differentiation and functional diversification [24], [25], [26], [27], [28], [29], [30], [31], [32]. The extensive diversity in the human NK cell repertoire, both within and between individuals, is known to be driven by a combination of genetic variations in receptor expression, homeostatic turnover and epigenetic reprogramming following the response to pathogenic challenges, in particular by human cytomegalovirus (CMV) [28], [31], [32], [33], [34], [35]. Much knowledge in this respect evolves from studies of NK cells in human peripheral blood. NK cells that reside in corresponding peripheral tissues including solid tumors are, however, still relatively less well-characterized [36]. In this respect, furthering our understanding of the biology of tumor-resident NK cells is essential to decipher their direct potential contribution to tumor control.
Herein, we review a series of findings relating to the complex interactions between NK cells and tumor cells. We discuss evidence for a direct role of NK cells in controlling human cancer development and/or progression, as well as studies showing enhanced cancer susceptibility and/or progression in patients with abnormal NK cell function. Together, these studies provide compelling evidence for an important role of NK cells in immunosurveillance against development and progression of cancers in humans. This concept encourages further efforts to develop new treatment options aimed at strengthening endogenous NK cell responses to tumor cells as well as designing protocols that utilize adoptive transfer of autologous and allogeneic NK cells to target human solid and hematological malignancies.
Section snippets
NK cell interactions with human tumor cells and the tumor microenvironment
NK cells can control cancers directly by interacting with tumor cells and indirectly by influencing the activities of other immune cells in the tumor microenvironment. Direct tumor cell lysis by NK cells is thought to be principally perforin-dependent, as extensively demonstrated in many experimental model systems [37]. However, NK cells can also induce tumor cell elimination through death receptor-mediated pathways such as TRAIL and FasL [38]. Further, activated NK cells produce numerous
NK cells with intact function prevent human cancer development and/or progression
In addition to the indisputable evidence for NK cell targeting of tumor cells in vitro and in vivo in mice, some intriguing clinical observations also point to the existence of NK cell-mediated immunosurveillance in human cancer. In Sections 3.1–3.3, we describe examples of studies indicating a direct role of NK cells in controlling human cancer development including a unique study in which reduction of cancer outcomes was observed on a population-based level in individuals with higher than
NK cells with inherited or acquired defects fail to prevent human cancer development and/or progression
Above, we described examples of studies indicating a direct role of NK cells in controlling human cancer development. In Section 2.3, we have discussed some aspects of tumor-induced suppression of NK cells. The latter included studies of downregulated NK cell-activation receptor expression. Many other related findings not covered in this review have focused on alterations in, e.g., the expression and function of signal-transducing proteins in tumor-associated NK cells [132], [133]. Below, in
Outlook – NK cells in the era of cancer immunotherapy
Cancer immunotherapy, including many cell-based therapies, is currently emerging as a central treatment-modality in a wide range of cancer types. It is obvious that T cell-mediated immune surveillance and recognition of neo-antigens are critical for the success of currently available checkpoint inhibitors directed against PD-1 and CTLA-4 [153]. In this review, we have outlined experimental and clinical evidence that NK cells and the innate immune system contribute to the control of malignant
Disclosure of potential conflicts of interest
K.J. Malmberg serves on the Scientific Advisory Board of Fate Therapeutics. H.G. Ljunggren serves on the Scientific Advisory Board of CellProtect Nordic Pharmaceuticals and HOPE Bio-Sciences; on the Board of Directors of Vycellix; and is a collaborator with Fate Therapeutics. The respective relationships have been reviewed and managed by Oslo University Hospital and Karolinska Institutet in accordance with the institutions’ conflict of interest policies.
Acknowledgements
The authors are supported grants from the Swedish Research Council, the Swedish Children’s Cancer Society, the Swedish Foundation for Strategic Research, the Swedish Cancer Society, the Swedish Society for Medical Research (SSMF), the Jeansson’s Foundations, Radiumhemmets Research foundation, the Knut and Alice Wallenberg Foundation, the Karolinska Institutet, the Karolinska University Hospital, the Norwegian Research Council, the Norwegian Cancer Society, the Norwegian Research Council, the
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