Natural Killer Cells and Cancer
Introduction
The ability of leukocytes, without deliberate immunization or activation, to kill certain tumors was first appreciated in the late 1960s and early 1970s, when investigators were attempting to generate tumor-antigen-specific cytotoxic T lymphocytes (CTL). Many labs working in the field experienced this “background” cytolytic activity in their in vitro cytotoxicity assays, and it soon became apparent that this was more than a technical artifact. Although there were numerous reports describing this activity, the first study to coin the term “natural” killer cells was an article by Kiessling, Klein, and Wigzell in 1975 (Kiessling et al., 1975). A distinguishing feature of NK cells is their ability to recognize and kill tumor cells that completely lack expression of MHC class I and II antigens. For a comprehensive review of the early developments in this field, the article by Trinchieri (1989) provides an excellent resource. Before discussing the role of NK cells in relationship to cancer, we will begin with a brief review of the cells responsible for “natural cytotoxicity,” their distinguishing characteristics, and their effector mechanisms.
NK cells are a lineage of lymphocytes, distinct from B and T cells in that they do not require recombinase activity for development or for the generation of their receptors involved in tumor cell recognition. Morphologically, they have been described as “large granular lymphocytes” because of the predominant azurophilic granules in the cytoplasm and their somewhat larger size than either resting B or T cells (Timonen et al., 1979); however, smaller, agranular NK cells also exist (Smyth et al., 1995). They comprise ∼ 5%–20% of peripheral blood lymphocytes, ∼5% of splenic lymphocytes, and ∼10% of hepatic lymphocytes, and they are present at lower frequencies in other hematopoietic tissues; for example, bone marrow, thymus, and lymph nodes. NK cells and T cells share many surface markers, likely because they arise from a common T⧸NK progenitor cell (Lian 2002, Spits 1995) and mediate many of the same effector functions (e.g., cell-mediated cytotoxicity and cytokine secretion). NK cell development requires IL-15 (Kennedy et al., 2000), and the cytolytic activity of NK cells against tumors can be substantially augmented by activation with IL-2, IL-12, IL-15, and IFN-α⧸β. NK cells are unable to produce any of these cytokines, but are dependent on other cell types to provide these factors. The activation of NK cells by IFN or cytokines or by cognate interactions with tumor cells also induces NK cells to transcribe and secrete certain cytokines and chemokines, including IFN-γ, granulocyte–macrophage hematopoietic colony-stimulating factors, tumor necrosis factor-α (TNF-α), and others.
Despite some similarities to T cells, NK cells are not dependent on the thymus for development, and they lack the T-cell antigen receptor and expression of the CD3 complex on the cell surface (Cooper 2001, Lanier 1992, Lian 2002, Spits 1995). They develop in the bone marrow from NK-progenitors, and cytokines, such as stem cell factor, FLT3 ligand, and IL-7 promote NK cell development, although they are not absolutely required (Colucci 2003, Lian 2002). IL-15, which is produced by the bone marrow stroma, is required for NK cell development and drives the final maturation process (Kennedy 2000, Mrozek 1996). The most commonly used surface marker to identify human NK cells, CD56, is expressed on all NK cells and a small subpopulation of memory T cells, as well as on neural tissues (Lanier et al., 1989a). However, CD56 is not involved in NK activation and killing, and its function on NK cells is still unknown. Murine NK cells do not express CD56 (although CD56 is expressed in the brain tissues in mice), but are often identified by using the anti-NK1.1 monoclonal antibody (mAb; Koo and Peppard, 1984) that reacts with NKR-P1C, or DX5 mAb (Arase et al., 2001), which detects VLA-2 (α2,β1 integrin). Another useful NK marker is CD16A (FcγRIII), a low-affinity Fc receptor for IgG, which is expressed on ∼90% of human NK cells and ∼50% of mouse NK cells (Trinchieri, 1989). CD16 enables NK cells to mediate antibody-dependent cell-mediated cytotoxicity against IgG-coated target cells, thereby conferring the antigen specificity of antibodies to NK cells.
Major progresses have been made in recent years in identifying receptors that allow NK cells to discriminate between normal and tumor- or virus-infected cells. NK cells can be activated and subsequently lyse target cells that have lost MHC-class I or that express subnormal levels of MHC-class I molecules, a common event following transformation or viral infection. As predicted by the “missing self” hypothesis (Karre et al., 1986), NK cells are usually prevented from attacking cells expressing self MHC class I because they express surface receptors for MHC class I delivering signals that inhibit NK function (Karlhofer 1992, Ravetch 2000). Studies of these MHC-specific inhibitory receptors have revealed an extraordinary complexity and specificity to prevent damage to normal healthy cells (Long 1999, Moretta 2001, Ravetch 2000). However, recent discovery of a group of activating surface receptors has solved the long-standing mystery of the “on” signal (Cerwenka 2001, Moretta 2001). Unlike T and B cells that possess a single dominant antigen receptor, NK cells use a variety of activating receptors with specialized signaling machinery to recognize and kill unhealthy and abnormal cells. These activating receptors, as will be reviewed later, may determine the distinct roles of NK cells in various phases of the immune responses, including tumor surveillance. The final disposition of an NK cell response is tightly regulated by an intricate balance between the opposing signals from the activating versus inhibitory receptors.
As their name implies, a predominant effector function of NK cells is cell-mediated cytotoxicity. This activity is predominantly mediated by the release of the contents of their cytoplasmic granules after encountering a “NK-sensitive” target cell. The process, called granule-mediated exocytosis, is directional, delivering the lethal payload directly into the interface between the NK cell and its target, thus preventing bystander killing (Henkart 1994, Trapani 2002). The granules in NK cells, as in CTL, contain perforin (a pore-forming protein with homology to complement factor 9) and several granzymes (proteases that act to cleave caspases in the target cells and initiate apoptosis by both caspase-dependent and caspase-independent mechanisms). Although in most circumstances the perforin and granzyme-mediated pathway is responsible for their lytic function, NK cells can also express certain members of the TNF family, including membrane and secreted TNFα, lymphotoxin, Fas ligand (FasL), and TNF-related-apoptosis-inducing ligand (TRAIL), that may also participate in the killing of certain sensitive target cells (reviewed in Trapani and Smyth, 2002).
NK cells also are an important source of cytokines and chemokines during an immune response. The production of these factors can be induced by cognate interactions between NK cells and tumors or virus-infected cells, or they can be triggered as a bystander event in response to cytokines or interferons in the local environment. Although NK cells are able secrete numerous cytokines (e.g., IFN-γ, GM-CSF, G-CSF, M-CSF, TNFα, IL-5, IL-10, IL-13, and others, Peritt et al., 1998) and chemokines (XCL1, CCL1, CCL3, CCL4, CCL5, CCL22, CXCL8, and others; Robertson, 2002), based on in vivo studies perhaps their most important function is their ability to rapidly produce IFN-γ early during an immune reaction (Biron et al., 1999). This pivotal cytokine is important in the activation of macrophages and in shaping the subsequent adaptive immune response. A critical role for IFN-γ in immune surveillance against cancer will be discussed later in this review.
Section snippets
NK Cells in Cancer
NK cells were originally defined as fresh-isolated white blood cells that are capable of lysing certain tumor targets, such as K562, a tumor cell line derived from a patient with chronic myelogenous leukemia (Ortaldo et al., 1977), or YAC-1, a Moloney tumor virus-induced lymphoma from A⧸Sn mice (Kiessling et al., 1975). Activation of NK cells with IL-2 or IFN-α⧸β further enhances their cytolytic function, resulting in killing a broad array of other tumor targets that are not lysed by resting NK
Perforin⧸Granzyme-Mediated Cytotoxicity
Perforin is stored in cytoplasmic granules, and on activation, NK and T cells secrete these cytolytic granules (reviewed in Podack 1991, Trapani 2002). Perforin monomers then insert into the plasma membrane of target cells and polymerize into pore-forming aggregates (Liu et al., 1995), which leads to osmotic lysis, granzyme entry, and killing of the target cells. Perforin and granzyme-mediated apoptosis is the principle pathway that NK cells use to kill tumors and virus-infected cells. Studies
Receptors Turning NK Cells “On” and “Off”
Unlike T and B cells, NK cells do not require the specialized gene arrangement machinery to assemble their receptor genes. However, they certainly are capable of discriminating between normal and abnormal cells. It has been well documented that NK cells preferentially kill certain cells that lack MHC class I expression (Ljunggren and Karre, 1985). NK cells are also able to reject MHC-incompatible bone marrow grafts, in particular when the donor graft lacks MHC molecules of the host (reviewed in
NK Cells in Tumor Immunosurveillance
Exposure to environmental stresses, such as pyrogens and inflammatory cytokines, may predispose cells to neoplastic transformation. Therefore, it is necessary for higher organisms to have sophisticated mechanisms to either repair such mutations or to recognize and eliminate the damaged cells that may result in tumor initiation. The concept of cancer immunosurveillance proposed by MacFarland Burnet and Lewis Thomas in the 1950s predicts that an unmanipulated immune system is capable of
Tumor Escape Mechanisms
The human NKG2D ligands, MICA⧸B and ULBP, and the mouse RAE-1 ligands for NKG2D are frequently overexpressed by tumors. There is convincing evidence that these ligands can trigger NK cell attack, so how do these tumors avoid being eliminated by NK cells and still grow in the body? One explanation is that tumors may secrete or shed proteins that downmodulate NK and T cell function, thereby evading adequate immune responses. A recent study by Groh et al. (2002) has provided strong evidence to
Conclusion
NK cells develop from bone marrow stem cells and are important cells in the innate immune system. They kill tumors predominantly through perforin-mediated pathways and by the secretion of cytokines, such as IFN-γ. A delicate balance of activating and inhibitory receptors on the cell surface of NK cells regulates their effector functions. Recent progress in understanding the structure and function of these receptors and their ligands has provided insights into NK-mediated tumor rejection, tumor
Acknowledgements
JW is an investigator at Chinese National Human Genome Center and is supported by Chinese National “863” grant 2002AA214111 and Shanghai Municipal Government S&T Commission grants 024319108, 02SYC007, and PKJ2002-11. LLL is an American Cancer Society Research Professor and is supported by NIH grants CA89189, CA89294, and CA095137. We thank Mark Smyth for helpful discussions.
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