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Targeting Natural Killer Cells and Natural Killer T Cells in Cancer

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Targeting Natural Killer Cells and Natural Killer T Cells in Cancer FOCUS ON TuMouR IMMunoLoGY & IMMunoTHERAPY REVIEWS Targeting natural killer cells and natural killer T cells in cancer Eric Vivier1,2,3,4, Sophie Ugolini1,2,3,5, Didier Blaise5,6,7, Christian Chabannon5,6,7 and Laurent Brossay8 Abstract | 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. The immune system is classically divided into innate and the antitumour effect of NK cells has been documented adaptive branches. The adaptive immune system can be in many models and instances. In vitro, mouse and defined by the presence of cells (B cells and T cells in human NK cells can kill a broad range of tumour cells of higher vertebrates) that can respond to many diverse haematopoietic and non-haematopoietic origin. In vivo, environmental antigens. This is achieved through the mouse NK cells can eliminate many transplantable and clonal expression of a colossal repertoire of B cell recep- spontaneous tumours9,10. Selective NK cell deficiencies 1 Centre d’Immunologie de 11 Marseille-Luminy, Université tors (BCRs) and T cell receptors (TCRs) with distinct are extremely rare , thus preventing the monitoring d’Aix-Marseille, Campus de antigen specificities, the diversity of which results from of cancer incidence in these patients, but also possibly Luminy Case 906, 13288 somatic DNA rearrangements. By contrast, the recogni- testifying to the physiological importance of NK cells. Marseille, France. tion of various assaults by cells of the innate immune Nevertheless, an epidemiological study has linked low 2 INSERM UMR 1104, system has been shown to depend on germline-encoded peripheral blood NK cell activity with increased cancer Marseille, France. 12 3CNRS, UMR 7280, Marseille, receptors. A recent paradigm shift in our understanding risk . In addition, NK cell infiltration into tumour tissue France. of immunity in mammals has resulted from the discovery is associated with better disease prognosis in non-small 4Assistance Publique – of the recognition receptors used by the innate immune cell lung carcinomas13,14, clear cell renal cell carcinomas15 Hôpitaux de Marseille, system, including the Toll-like receptors (TLRs)1–3. and colorectal cancer16. Observations in patients with Hôpital de la Conception, 13385 Marseille, France. Besides conventional B and T cells, several populations advanced gastrointestinal stromal tumours treated with 4 5 Institut Paoli-Calmettes, of innate lymphoid cells (ILCs) were recently identified . ILC imatinib mesylate support the hypothesis that NK cells Centre de Lutte Contre le populations include various cells of the innate immune exert antitumour effects not only through direct cyto­ Cancer, Marseille, France. system, such as lymphoid tissue-inducer (LTi) cells, but lytic activity, but also indirectly through their ability to 6 Université d’Aix-Marseille, also cells that produce interleukin‑5 (IL‑5), IL‑13, IL‑17 produce cytokines such as IFNγ17. Marseille, France. 7INSERM CBT‑510, Centre and/or IL‑22 and that help to initiate immune responses Natural killer T (NKT) cells have been classified into 18 d’Investigations Cliniques en to pathogens. Natural killer cells (NK cells) are now recog- four different groups . Only type I and type II NKT cells Biothérapie, Marseille, France. nized as a subset of cytotoxic ILCs that express the trans­ are CD1d‑restricted; they respond to CD1d‑expressing 8Department of Molecular cription factor E4BP4 (E4 promoter-binding protein 4; cells and are absent in CD1d‑deficient mice18 (BOX 1). Microbiology and Immunology, Division of also known as NFIL3). NK cells secrete cytokines, such The most-studied group — known as type I NKT cells Biology and Medicine, as interferon‑γ (IFNγ), that participate in the shaping of or invariant NKT cells (iNKT cells) — is well conserved in Brown University, Providence, the adaptive immune response5. An important feature mammals18. iNKT cells develop in the thymus and arise Rhode Island, USA. of NK cells is their capacity to distinguish stressed cells from the same common lymphoid precursor pool as Correspondence to E.V. and L.B. (such as tumour cells, infected cells and cells that have conventional T cells19,20. After αβ T cell lineage commit- e-mails: [email protected]; undergone physical or chemical injuries) from healthy ment and the generation of double-positive thymocytes, [email protected] cells. NK cells were initially identified through their abil- the iNKT cell and conventional T cell selection pathways doi:10.1038/nri3174 ity to kill tumour cells (hence their name)6–8. Since then, diverge21,22. iNKT cell precursors are selected following NATURE REVIEWS | IMMUNOLOGY VOLUME 12 | APRIL 2012 | 239 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Box 1 | CD1d‑restricted T cells and the activation of iNKT cells Cells that are activated in response to antigens presented by the MHC class I‑like molecule CD1d are highly conserved in mammals and have been classified as type I and type II natural killer T (NKT) cells18. Type I NKT cells are also known as invariant NKT (iNKT) cells and express a semi-invariant T cell receptor (TCR), whereas type II NKT cells express a more diverse TCR repertoire. iNKT cells have been characterized using CD1d tetramers loaded with α‑galactosylceramide (αGalCer) in both mice and humans, and also by using the 6B11 monoclonal antibody in humans218–220. By contrast, the functions of type II NKT cells are unclear and have only been indirectly examined by comparing the phenotypes and Toll-like receptors immune responses of CD1d‑deficient and J 18‑deficient animals, which lack iNKT and type II NKT cells and only (TLRs). A family of α evolutionarily conserved iNKT cells, respectively. pattern-recognition receptors. iNKT cell frequencies are lower in humans than in mice, but the frequencies of type II NKT cells in both species are These molecules are located unknown owing to a lack of reliable tools to identify these cells. Although all iNKT cells can be identified by staining with intracellularly and at the cell CD1d tetramers, recent data indicate that there are several distinct subsets of iNKT cells with different functions and surface of macrophages, phenotypes. Notably, although most iNKT cells express the Vα14–Jα18 TCR α‑chain, an αGalCer-reactive NKT cell subset dendritic cells, B cells and that expresses a Vα10–Jα50 TCR α‑chain was recently identified221. intestinal epithelial cells. Their iNKT cells are unique because they have the ability to respond both as innate cells, with minimal TCR involvement, natural ligands are molecules and as memory-like cells through the engagement of their semi-invariant TCR. TCR-dependent activation of iNKT cells that are found in bacteria, has been extensively studied using the strong agonist GalCer, which is presented on CD1d. In this case, the iNKT cell viruses and fungi. α response is CD1d dependent, and pro-inflammatory cytokines are dispensable. Interestingly, however, iNKT cell-mediated Innate lymphoid cells protection against pathogens that express antigens recognized by the invariant TCR of iNKT cells predominantly (ILCs). A group of cells of depends on pro-inflammatory cytokines, such as interleukin‑12 (IL‑12)47. lymphoid origin that includes The indirect activation of iNKT cells has recently been characterized during viral infection and is induced in the NK cells, LTi cells and other presence of large amounts of pro-inflammatory cytokines, such as IL‑12, IL‑18 and interferon-α (IFNα)43–45. In this non‑T, non‑B cells that produce setting, iNKT cells functionally resemble classical natural killer (NK) cells and produce mostly T helper 1 (TH1)-type distinct cytokines such as IL‑5, cytokines. iNKT cells can also be activated by combined exposure to pro-inflammatory cytokines and CD1d‑dependent IL‑13 or IL‑17. TCR stimulation. This has been reported to occur during infection with certain bacteria (such as Salmonella enterica subsp. enterica serovar Typhimurium, Staphylococcus aureus and Mycobacterium tuberculosis) that do not themselves Natural killer cells (NK cells). Non‑T, non‑B express glycolipid agonists for the invariant TCR. Instead, it is thought that iNKT cells become activated in this setting 222 lymphocytes that can mediate in response to endogenous glycosphingolipids (such as β-d-glucopyranosylceramide ) that are presented by natural killing of prototypical pathogen-activated dendritic cells223–226. NK cell-sensitive targets (such as K562 cells in humans and YAC1 cells in mice) and/or produce IFNγ. In humans, rearrangement of the TCR α-chain gene and express a Here, we discuss recent research on the role of NK NK cells typically have a NKp46+CD56+CD3– semi-invariant TCR (Vα14–Jα18 in mice; Vα24–Jα18 in and NKT cells in the control of tumours, with a special 21,23–26 phenotype, and they are humans) . In contrast to conventional T cells, which emphasis on how the molecular dissection of their mode NKp46+NK1.1+CD3–
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