Natural-killer (NK) cells are important components of the innate immune system.
There is evidence of tumour rejection by NK cells. NK cells act against tumour initiation, growth and metastasis in rodents and humans.
NK cells suppress tumour cells though a variety of effector mechanisms, including the perforin/granzyme-containing granule-mediated pathway, death-receptor pathway and IFN-γ-mediated pathway.
NK-cell functions are regulated by the balance of inhibitory and activating signals that they receive through their various classes of receptor. Each class and functional role in controlling tumour immunity is discussed.
Co-stimulatory molecules that are expressed by NK cells further serve to control NK-cell antitumour function and evoke subsequent adaptive T-cell immunity.
The cytokine and chemokine environment serves to define the differentiation, proliferation and recruitment of NK cells.
NK cells might influence the development of adaptive immunity through cross-talk with antigen-presenting dendritic cells.
The clinical use of NK cells in patients has undergone 15 years of refinement. With the description of key developmental factors for NK cells and the definition of immunoglobulin-like receptors for MHC class I, more sophisticated approaches to NK-cell transfer are yielding impressive antitumour responses.
Natural-killer (NK) cells form a first line of defence against pathogens or host cells that are stressed and/or cancerous. NK cells express surface receptors that receive signals from the environment and determine their response to foreign or malignant cells. NK cells respond to these signals by producing effector molecules that can both directly suppress tumour growth and convey important information to the rest of the immune system. We have only recently begun to appreciate the potential for NK cells to be rationally manipulated in the treatment of human cancers.
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We thank J. Trapani and D. Godfrey for their collaboration, and the Human Frontiers in Science Program and National Health and Medical Research Council of Australia for supporting our work.
- INNATE IMMUNE SYSTEM
Non-adaptive immunity that involves epithelial barriers, phagocytic cells such as neutrophils and macrophages, the complement system, natural-killer cells, and cytokines that coordinate the actions of these innate cells. These components rapidly respond and protect the host from initial infections, without prior priming with specific antigens.
Movement out of the vascular compartment into interstitial spaces.
- NON-CLASSICAL MHC CLASS I MOLECULES
These are also known as major histocompatibility complex (MHC) class 1b glycoproteins. They differ from classical MHC molecules by specific patterns of transcription, protein expression and immunological functions. They are more specialized in function than classical MHC molecules and, in some cases, interact with more limited subsets of lymphoid cells, such as CD1d and natural-killer T cells.
- MYCOBACTERIUM BOVIS BACILLUS CALMETTE–GUERIN
An attenuated, non-virulent strain of M. bovis that is used as a vaccine against tuberculosis. It acts as an inflammatory substance that has direct effects on the tumour. It also activates antigen-presenting cells and acts as an adjuvant in the immune stimulation of cancer patients. It has been used most successfully in the treatment of bladder cancer.
- T HELPER 1 AND T HELPER 2 CYTOKINES
These are two patterns of cytokine production that have been described for CD4+ T cells. The TH1 pattern includes pro-inflammatory cytokines (typified by interferon-γ), whereas the TH2 pattern includes cytokines such as interleukin (IL)-4, IL-5 and IL-13.
- NATURAL-KILLER T CELLS
(NKTs). A unique T-cell lineage that expresses NK-cell markers such as CD161 and recognizes glycolipid antigens in the context of the non-classical MHC molecule CD1d. NKT cells are potent producers of immunoregulatory cytokines, and have been implicated in autoimmune diseases, viral infections and tumour control in mice and humans.
A mismatch of tissue or cells between donor and recipient (of the same species but genetically non-identical)
- SIGNAL PEPTIDES
Antigens are processed and presented on the surface of the cell as peptide fragments that are bound within the cleft of molecules encoded by the major histocompatibility complex genes. Peptides include those that are derived from the signal sequence of proteins (such as from the starting methionine to the mature amino terminus of the protein).
- ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY
(ADCC). A mechanism by which natural-killer (NK) cells are targeted to IgG-coated cells, resulting in lysis of the antibody-coated cells. A specific receptor for the constant region of IgG, called FcγRIII (CD16), is expressed on the NK-cell membrane and mediates the ADCC.
- γδ T CELLS
T cells that express a T-cell receptor (TCR) that are composed of γ and δ chains and are most abundant at epithelial tissue barriers. The forms of antigen that are recognized by γδ TCR are poorly understood, although some γδ T cells recognize antigens that are presented by non-classical major histocompatibility complex class I molecules.
- Fc RECEPTOR
A cell-surface receptor that is specific for the carboxy-terminal constant region of an Ig molecule. Fc receptors are typically multichain complexes that include Ig binding components and signalling components. Several types of Fc receptors exist, including those that are reactive with different IgG isotypes: IgE and IgA. Fc receptors mediate many of the cell-dependent effector functions of antibodies, including antigen-induced activation of mast cells, phagocytosis of antibody-bound antigens, and targeting and activation of natural-killer cells.
- T-CELL MEMORY
The unique property of the T-cell-mediated adaptive immune system to respond more rapidly, with greater magnitude, and more effectively to a repeated exposure to an antigen, compared with the first exposure.
- ADAPTIVE T-CELL IMMUNITY
T-cell mediated immunity, which is stimulated by presentation of processed antigen. In contrast to innate immunity, adaptive immunity is characterized by exquisite specificity for distinct macromolecules and 'memory'.
- HIGH ENDOTHELIAL VENULES
(HEVs). Specialized venules that are the sites of lymphocyte extravasation from the blood into the stroma of a peripheral lymph node or mucosal lymphoid tissue. HEVs are lined by endothelial cells that protrude into the vessel lumen and express unique adhesion molecules that are involved in binding naive T cells.
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Smyth, M., Hayakawa, Y., Takeda, K. et al. New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer 2, 850–861 (2002). https://doi.org/10.1038/nrc928
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