Natural killer (NK) cells have the ability to lyse tumour cells without the requirement for prior immune sensitization of the host. NK-cell recognition of target cells is tightly regulated by processes involving the integration of signals delivered from multiple activating and inhibitory receptors.
Insights into the molecular specificities that regulate NK-cell function have led to new possibilities to design NK-cell-based immunotherapeutic strategies against human cancer. Strategies of NK-cell immunotherapy include activation of endogenous NK cells, NK-cell-mediated graft-versus-tumour (GVT) effects in the context of haematopoietic allogeneic stem-cell transplantation (SCT), and adoptive transfer of allogeneic NK cells.
Endogenous NK cells may be activated by cytokines, immunomodulatory drugs, and agonists of activating receptors or by blockade of inhibitory killer-cell immunoglobulin-like receptor (KIR) with monoclonal antibodies, thereby augmenting tumour-cell recognition by NK cells. NK cells may also be genetically engineered to shift the balance towards NK-cell activation.
NK cells have been shown to mediate GVT effects in allogeneic haematopoietic SCT. Future criteria for donor selection may involve the selection of KIR–ligand-mismatched donors with a large alloreactive NK-cell subset.
Conditioning regimens will probably be required for survival and in vivo expansion of adoptively transferred NK cells. Apart from preventing rejection, such regimens may eradicate regulatory T cells and promote access to homeostatic cytokines, including IL-15.
Tumour-cell susceptibility to NK-cell lysis may be predicted by characterizing the expression of activating receptor ligands on tumour cells, as well as the expression of ligands for inhibitory receptors (MHC class I molecules). Such phenotypic analysis may be combined with direct testing of freshly isolated tumour cells for their susceptibility to NK-cell lysis ex vivo.
Combinatorial therapies, in which NK cells represent one important mediator, may further potentiate the clinical efficacy of NK-cell immunotherapy.
Current insights into the molecular specificities that regulate natural killer (NK)-cell function suggest that it might be possible to design NK-cell-based immunotherapeutic strategies against human cancer. Here, we describe evidence for NK-cell targeting of human tumours and address crucial questions that, in our opinion, require consideration for the development of successful NK-cell-based therapies. Appropriately used, we predict that NK cells will have a role, both directly and in combination with other treatment modalities, in future treatment of cancer.
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We thank our colleagues S. Applequist, B. Baumann, N. Björkström, Y. Bryceson, M. Carlsten, C. Fauriat, and P. Ljungman for critically reading the manuscript, as well as other members of our laboratory for fruitful discussions. We are supported by the Swedish Foundation for Strategic Research, the Swedish Research Council, the Swedish Cancer Society, the Tobias Foundation, the Swedish Children's Cancer Foundation, the Cancer Society of Stockholm, the Karolinska Institutet and the Karolinska University Hospital. K.J.M. is a research fellow at the Royal Swedish Academy of Sciences.
The authors declare no competing financial interests.
- Antibody-dependent cell-mediated cytotoxicity
(ADCC). A mechanism by which natural killer (NK) cells are targeted to IgG-coated cells, resulting in the lysis of the antibody-coated cells. The low-affinity Fc receptor for IgG (FcγRIII; also known as CD16), is expressed at the surface of NK cells and mediates ADCC.
- Thalidomide and Lenalidomide
Thalidomide (α-N-phthalimidoglutarimide) is a derivative of glutamic acid. It is pharmacologically classified as an immunomodulatory drug because of its ability to change the expression of various cytokines and to co-stimulate immune effector cells including natural killer cells. Lenalidomide is a 4-aminoglutaramide analogue of thalidomide with enhanced immunomodulatory effects and a favourable toxicity profile compared with its parent compound.
- Immunostimulatory DNA complexes
Synthetic DNA oligonucleotides containing unmethylated CpG motifs (CpG-ODN) that provide a danger signal to the immune system by mimicking the activity of bacterial DNA. CpG-ODN trigger rapid responses by innate immune cells including plasmacytoid dendritic cells and natural killer cells.
A functional maturation process of NK cells involving the recognition of host MHC class I molecules by inhibitory NK-cell receptors. Lack of such functional maturation has been suggested as one mechanism behind the hyporesponsiveness of NK cells that do not express inhibitory receptors to host MHC class I molecules.
- Replicative senescence
A growth-arrest state eventually reached by cells that have undergone repetitive proliferation in vitro or in vivo, which is characterized by functionally active cells that lack, or have a reduced, proliferative capacity. Senescent immune cells are more common in elderly people and in patients with chronic inflammatory diseases.
- Regulatory T cells
(TReg cells). A small population of CD4+ T cells that expresses the transcription factor forkhead box P3 (FOXP3) and has regulatory (that is, suppressor) activity towards T-cell and natural-killer-cell activation. An absence of functional TReg-cells is associated with severe autoimmunity.
A DNA-alkylating agent that is used widely as an antitumour agent or an immunosuppressive agent. Cyclophosphamide has been shown to destroy certain subsets of lymphocytes preferentially, including B cells and regulatory cells.
A purine analogue that acts as an inhibitory substrate for ribonucleotide reductase, DNA polymerases, DNA ligase I, and DNA primase. It affects DNA synthesis and transcription. Fludarabine induces cell death, particularly in leukaemic cells, and is commonly used in the treatment of indolent leukaemia and lymphoma. Fludarabine has also been incorporated into reduced intensity preparative regimens for haematopoietic stem-cell transplantation.
- Small interfering RNA
(siRNA). Short double-stranded RNAs of 19–23 nucleotides that induce RNA interference, a post-transcriptional process that leads to gene silencing in a sequence-specific manner.
- Bispecific antibodies
These are antibodies that are derived from the recombination of variable domains from two antibodies with different specificities. Bispecific antibodies have been used to redirect cytotoxic immune cells to tumour cells.
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Ljunggren, HG., Malmberg, KJ. Prospects for the use of NK cells in immunotherapy of human cancer. Nat Rev Immunol 7, 329–339 (2007). https://doi.org/10.1038/nri2073
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