Natural killer (NK) and natural killer T (NKT) cells are subsets of lymphocytes that share some phenotypical and functional similarities.
NK and NKT cells can rapidly respond to the presence of tumour cells and participate in antitumour immune responses.
Innovative anticancer therapies that are based on the manipulation of NK cells include allogeneic haematopoietic stem cell transplantation, infusion of NK cells and monoclonal antibody-based treatments.
The combined transfer of invariant NKT cells and α-galactosylceramide-pulsed dendritic cells induces substantial antitumour immunity in patients.
Natural killer (NK) cells and natural killer T (NKT) cells are subsets of lymphocytes that share some phenotypical and functional similarities. Both cell types can rapidly respond to the presence of tumour cells and participate in antitumour immune responses. This has prompted interest in the development of innovative cancer therapies that are based on the manipulation of NK and NKT cells. Recent studies have highlighted how the immune reactivity of NK and NKT cells is shaped by the environment in which they develop. The rational use of these cells in cancer immunotherapies awaits a better understanding of their effector functions, migratory patterns and survival properties in humans.
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E. V. and S. U. are supported by funds from a THINK European Research Council advanced grant, the Agence Nationale de la Recherche and the Ligue Nationale Contre le Cancer, and by institutional grants from INSERM, CNRS and the Université d'Aix-Marseille to the Centre d'Immunologie de Marseille-Luminy. E.V. is a scholar of the Institut Universitaire de France, and a co-founder of and shareholder in Innate Pharma. D.B. and C.C. are supported by grants from the Institut Paoli-Calmettes, the Programme Hospitalier de Recherche Clinique (PHRC) and the Association pour la Recherche sur le Cancer. L.B. is supported by US National Institutes of Health research grants AI46709 and AI058181.
Eric Vivier is a co-founder of and shareholder in Innate Pharma.
- Toll-like receptors
(TLRs). A family of evolutionarily conserved pattern-recognition receptors. These molecules are located intracellularly and at the cell surface of macrophages, dendritic cells, B cells and intestinal epithelial cells. Their natural ligands are molecules that are found in bacteria, viruses and fungi.
- Innate lymphoid cells
(ILCs). A group of cells of lymphoid origin that includes NK cells, LTi cells and other non-T, non-B cells that produce distinct cytokines such as IL-5, IL-13 or IL-17.
- Natural killer cells
(NK cells). Non-T, non-B lymphocytes that can mediate natural killing of prototypical NK cell-sensitive targets (such as K562 cells in humans and YAC1 cells in mice) and/or produce IFNγ. In humans, NK cells typically have a NKp46+CD56+CD3− phenotype, and they are NKp46+NK1.1+CD3− in the C57BL/6 mouse strain and NKp46+CD3− in all mouse strains.
- Imatinib mesylate
A first of its class tyrosine kinase inhibitor with clinical activity against chronic myeloid leukaemia associated with the t(9;22) reciprocal translocation. The introduction of imatinib mesylate into clinical practice at the end of the twentieth century induced a rapid shift in medical practices, such that allogeneic haematopoietic stem cell transplantation was abandoned as the standard treatment for this type of cancer.
An MHC-like molecule that associates with β2-microglobulin and presents lipids.
- Invariant NKT cells
(iNKT cells). A subset of T cells that possess a semi-invariant TCR. In both mice and humans, iNKT cells recognize ligands presented by CD1d.
A member of the T-box family of transcription factors. It is a master switch in the development of T helper 1 (TH1) cells through its ability to regulate the expression of the IL-12 receptor, to inhibit signals that promote TH2 cell development and to promote the production of interferon-γ.
- Perforin- and granzyme-mediated mechanisms
Granzymes are serine proteases that are found primarily in the cytoplasmic granules of cytotoxic T lymphocytes and NK cells. They enter target cells through perforin pores and then cleave and activate intracellular caspases to induce target-cell apoptosis.
- CD95–CD178 pathway
CD178 (also known as FAS ligand) binds to CD95 (also known as FAS). This results in the formation of a death-inducing signalling complex and the subsequent activation of caspases, which promote the apoptosis of the CD95-expressing target cell.
- Immunoreceptor tyrosine-based inhibitory motif
(ITIM). A motif that is present in the cytoplasmic domains of several inhibitory receptors. After ligand binding, ITIMs are phosphorylated on their tyrosine residues and recruit lipid or tyrosine phosphatases.
- DNA damage response
A cell response triggered by DNA damage, such as single or double strand breaks. The DNA damage response stops cell cycle progression to enable repair before the damage is transmitted to progeny cells. Checkpoints in the mammalian DNA damage response are controlled by the PI3K-related kinases ATM and ATR.
- Immunoreceptor tyrosine-based activation motifs
(ITAMs). Activating receptors often have ITAMs consisting of a consensus amino-acid sequence with paired tyrosines and leucines (Yxx(I/L)x6–12Yxx(I/L)). These motifs are normally located in the cytoplasmic domains of ligand-binding transmembrane receptors (such as FcɛRI and the TCR), and they mediate interactions between the transmembrane receptor complex and protein tyrosine kinases, which are required to initiate early and late signalling events.
- Antibody-dependent cellular cytotoxicity
(ADCC). A mechanism used by leukocytes that express Fc receptors to kill antibody-coated target cells.
A chimeric monoclonal antibody that is specific for the CD20 molecule, which is primarily expressed by B cells. Rituximab is the most frequently used antibody therapy for patients with cancer.
- Graft-versus-leukaemia effect
The antitumour activity of donor T cells against residual leukaemic cells of the graft recipient following (allogeneic) bone marrow transplantation.
- Graft-versus-host disease
(GVHD). Tissue damage in a recipient of allogeneic transplanted tissue (usually a bone marrow transplant) that results from the activity of donor cytotoxic T lymphocytes that recognize the tissue of the recipient as foreign. GVHD varies markedly in severity, but can be life threatening in severe cases. Typically, damage to the skin and gut mucosa leads to clinical manifestations.
(Also known as cyclosporin A). A commonly used immunosuppressive drug that blocks calcineurin A and thereby inhibits T cell activation. It is used to prevent the rejection of transplanted organs and to treat some inflammatory diseases. Ciclosporin is widely used to prevent graft-versus-host disease following allogeneic haematopoietic stem cell transplantation.
- Reduced-intensity conditioning regimens
Regimens that use less chemotherapy and radiation than is normally used for myeloablation.
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Vivier, E., Ugolini, S., Blaise, D. et al. Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol 12, 239–252 (2012). https://doi.org/10.1038/nri3174
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