Natural killer cell biology: an update and future directions.
01 Sep 2013-The Journal of Allergy and Clinical Immunology (NIH Public Access)-Vol. 132, Iss: 3, pp 536-544
TL;DR: Recent discoveries are reviewed, including a better comprehension of the "education" of NK cells to achieve functional competence during their maturation and the discovery of "memory" responses by NK cells, suggesting that they might also contribute to adaptive immunity.
Abstract: Natural killer (NK) cells constitute a minor subset of normal lymphocytes that initiate innate immune responses toward tumor and virus-infected cells. They can mediate spontaneous cytotoxicity toward these abnormal cells and rapidly secrete numerous cytokines and chemokines to promote subsequent adaptive immune responses. Significant progress has been made in the past 2 decades to improve our understanding of NK cell biology. Here we review recent discoveries, including a better comprehension of the "education" of NK cells to achieve functional competence during their maturation and the discovery of "memory" responses by NK cells, suggesting that they might also contribute to adaptive immunity. The improved understanding of NK cell biology has forged greater awareness that these cells play integral early roles in immune responses. In addition, several promising clinical therapies have been used to exploit NK cell functions in treating patients with cancer. As our molecular understanding improves, these and future immunotherapies should continue to provide promising strategies to exploit the unique functions of NK cells to treat cancer, infections, and other pathologic conditions.
Citations
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TL;DR: This review focuses on recent advances in NK cell engineering, particularly on preclinical evidence suggesting that NK cells may be as effective as T cells in recognizing and killing targets after genetic modification.
312 citations
Cites background from "Natural killer cell biology: an upd..."
...In this context, the NK cell does not receive inhibitory signals.(19,20) In parallel, cellular stress and DNA damage, both of which occur in cells during viral or malignant transformation, result in upregulation of “stress ligands” that can be recognized by activating NK receptors, resulting in a positive signal for NK cells to kill the target....
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TL;DR: The current progress in NK cell-based immunotherapeutic strategies (NK cells combined with stimulants, adoptive transfer of NK cells, CAR-NK cells, and NK EVs) for the treatment of cancers are reviewed, and the challenges and opportunities for opening a new horizon for cancer immunotherapy are discussed.
Abstract: Cancer immunotherapy has been firmly established as a new milestone for cancer therapy, with the development of multiple immune cells as therapeutic tools. Natural killer (NK) cells are innate immune cells endowed with potent cytolytic activity against tumors, and meanwhile act as regulatory cells for the immune system. The efficacy of NK cell-mediated immunotherapy can be enhanced by immune stimulants such as cytokines and antibodies, and adoptive transfer of activated NK cells expanded ex vivo. In addition, NK cells can arm themselves with chimeric antigen receptors (CARs), which may greatly enhance their anti-tumor activity. Most recently, extracellular vesicles (EVs) derived from NK cells show promising anti-tumor effects in preclinical studies. Herein, we carefully review the current progress in these NK cell-based immunotherapeutic strategies (NK cells combined with stimulants, adoptive transfer of NK cells, CAR-NK cells, and NK EVs) for the treatment of cancers, and discussed the challenges and opportunities for opening a new horizon for cancer immunotherapy.
269 citations
TL;DR: The specific metabolic requirements for NK cell responses and how defects in NK cell metabolism may contribute to NK cell dysfunction in chronic disease are described.
Abstract: Natural killer (NK) cells are lymphocytes with important roles in innate and adaptive immune responses to tumours and viral infection. However, in certain chronic diseases, including obesity and cancer, NK cell functional responses are impaired. Recently, research has highlighted the importance of NK cell metabolism in facilitating robust NK cell effector functions. This Review describes our current understanding of mouse and human NK cell metabolism and the key signalling pathways that mediate metabolic responses in NK cells. Furthermore, it explores how defects in metabolism can contribute to the generation of dysfunctional NK cells in chronic disease. Finally, the potential for new therapeutic strategies targeting cellular metabolism is discussed. As in other immune cells, the metabolic pathways in natural killer (NK) cells must be configured to meet the demands of their effector functions. This Review describes the specific metabolic requirements for NK cell responses and how defects in NK cell metabolism may contribute to NK cell dysfunction in chronic disease.
218 citations
TL;DR: This review focuses on recent advances in the field of NK cell immunotherapy, including augmentation of antibody-dependent cellular cytotoxicity, manipulation of receptor-mediated activation, and adoptive immunotherapy with ex vivo-expanded, chimeric antigen receptor (CAR)-engineered, or engager-modified NK cells.
Abstract: Natural killer (NK) cells are essential components of the innate immune system and play a critical role in host immunity against cancer. Recent progress in our understanding of NK cell immunobiology has paved the way for novel NK cell-based therapeutic strategies for the treatment of cancer. In this review, we will focus on recent advances in the field of NK cell immunotherapy, including augmentation of antibody-dependent cellular cytotoxicity, manipulation of receptor-mediated activation, and adoptive immunotherapy with ex vivo-expanded, chimeric antigen receptor (CAR)-engineered, or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack non-hematopoietic tissues, suggesting that an NK-mediated antitumor effect can be achieved in the absence of graft-vs.-host disease. Despite reports of clinical efficacy, a number of factors limit the application of NK cell immunotherapy for the treatment of cancer, such as the failure of infused NK cells to expand and persist in vivo. Therefore, efforts to enhance the therapeutic benefit of NK cell-based immunotherapy by developing strategies to manipulate the NK cell product, host factors, and tumor targets are the subject of intense research. In the preclinical setting, genetic engineering of NK cells to express CARs to redirect their antitumor specificity has shown significant promise. Given the short lifespan and potent cytolytic function of mature NK cells, they are attractive candidate effector cells to express CARs for adoptive immunotherapies. Another innovative approach to redirect NK cytotoxicity towards tumor cells is to create either bispecific or trispecific antibodies, thus augmenting cytotoxicity against tumor-associated antigens. These are exciting times for the study of NK cells; with recent advances in the field of NK cell biology and translational research, it is likely that NK cell immunotherapy will move to the forefront of cancer immunotherapy over the next few years.
210 citations
Journal Article•
TL;DR: In this paper, the authors used a mouse model of cytomegalovirus infection to show that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100fold in the spleen and 1,000-fold in liver after infection.
Abstract: In an adaptive immune response, naive T cells proliferate during infection and generate long-lived memory cells that undergo secondary expansion after a repeat encounter with the same pathogen. Although natural killer (NK) cells have traditionally been classified as cells of the innate immune system, they share many similarities with cytotoxic T lymphocytes. We use a mouse model of cytomegalovirus infection to show that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100-fold in the spleen and 1,000-fold in the liver after infection. After a contraction phase, Ly49H-positive NK cells reside in lymphoid and non-lymphoid organs for several months. These self-renewing 'memory' NK cells rapidly degranulate and produce cytokines on reactivation. Adoptive transfer of these NK cells into naive animals followed by viral challenge results in a robust secondary expansion and protective immunity. These findings reveal properties of NK cells that were previously attributed only to cells of the adaptive immune system.
194 citations
References
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TL;DR: A low dose of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission.
Abstract: We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.
3,204 citations
TL;DR: It is shown that donor-versus-recipient natural killer (NK)–cell alloreactivity could eliminate leukemia relapse and graft rejection and protect patients against GVHD in human transplants and in mice, the pretransplant infusion of alloreactive NK cells obviated the need for high-intensity conditioning and reduced GV HD.
Abstract: T cells that accompany allogeneic hematopoietic grafts for treating leukemia enhance engraftment and mediate the graft-versus-leukemia effect. Unfortunately, alloreactive T cells also cause graft-versus-host disease (GVHD). T cell depletion prevents GVHD but increases the risk of graft rejection and leukemic relapse. In human transplants, we show that donor-versus-recipient natural killer (NK)-cell alloreactivity could eliminate leukemia relapse and graft rejection and protect patients against GVHD. In mice, the pretransplant infusion of alloreactive NK cells obviated the need for high-intensity conditioning and reduced GVHD. NK cell alloreactivity may thus provide a powerful tool for enhancing the efficacy and safety of allogeneic hematopoietic transplantation.
3,132 citations
TL;DR: Although NK cells might appear to be redundant in several conditions of immune challenge in humans, NK cell manipulation seems to hold promise in efforts to improve hematopoietic and solid organ transplantation, promote antitumor immunotherapy and control inflammatory and autoimmune disorders.
Abstract: Natural killer (NK) cells are effector lymphocytes of the innate immune system that control several types of tumors and microbial infections by limiting their spread and subsequent tissue damage. Recent research highlights the fact that NK cells are also regulatory cells engaged in reciprocal interactions with dendritic cells, macrophages, T cells and endothelial cells. NK cells can thus limit or exacerbate immune responses. Although NK cells might appear to be redundant in several conditions of immune challenge in humans, NK cell manipulation seems to hold promise in efforts to improve hematopoietic and solid organ transplantation, promote antitumor immunotherapy and control inflammatory and autoimmune disorders.
3,108 citations
"Natural killer cell biology: an upd..." refers background in this paper
...536 WHAT ARE NATURAL KILLER CELLS? MORE THAN THE NAME IMPLIES Although named for their capacity to mediate spontaneous ‘‘natural’’ cytotoxicity toward certain tumor and virus-infected cells, NK cells are also a major source of the type 1 cytokine IFNg, as well as TNF-a, GM-CSF, and other cytokines and chemokines.(1,2) Production of these soluble factors by NK cells in early innate immune responses significantly influences the recruitment and function of other hematopoietic cells....
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TL;DR: An activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses is defined.
Abstract: Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for gammadelta T cells and is frequently expressed in epithelial tumors. A receptor for MICA was detected on most gammadelta T cells, CD8+ alphabeta T cells, and natural killer (NK) cells and was identified as NKG2D. Effector cells from all these subsets could be stimulated by ligation of NKG2D. Engagement of NKG2D activated cytolytic responses of gammadelta T cells and NK cells against transfectants and epithelial tumor cells expressing MICA. These results define an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses.
2,916 citations
"Natural killer cell biology: an upd..." refers background in this paper
...This diversity is compounded by inheritance of different haplotypes of KIR or Ly49 genes by subjects and minor allelic polymorphisms, which further increase the variability of expression and ligand recognition by these inhibitory receptors within human and mouse populations.26 Activating receptors expressed on NK cells include FcgRIIIA, activating forms of KIRs (KIR2DS and KIR3DS), 2B4, NKG2D, and the NCRs called NKp30, NKp44, and NKp46 (Table I).20,27 FcgRIIIA (CD16) can trigger antibody-dependent cellular cytotoxicity (ADCC) on encountering target cells opsonized with IgG, whereas NKG2D and NCRs appear to be the most relevant receptors that stimulate responses to tumor target cells.28 Ligands for several of these receptors are still undefined, but several known ligands are upregulated on stressed cells, such as MICA and MICB ligands for NKG2D and the B7-H6 ligand for NKp30....
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...Ligands for several of these receptors are still undefined, but several known ligands are upregulated on stressed cells, such as MICA and MICB ligands for NKG2D and the B7-H6 ligand for NKp30.(29,30) Integrins also play important roles in mediating adhesion to target cells, and integrin-mediated signaling is important for stimulating the NK cell activation that triggers targeted degranulation....
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TL;DR: In vivo studies with H-2-deficient targets that support the 'missing self' hypothesis are reviewed and testable predictions for how MHC class I molecules act in cases where they control a rate-limiting step in the NK cell-target interaction are derived.
2,559 citations
"Natural killer cell biology: an upd..." refers background in this paper
...The predominant cytolytic targets of NK cells are uncommon cells that have downregulated expression of class IMHC (MHC-I), which is expressed on nearly every healthy cell of the body.(16) MHC-I loss is a fairly common mechanism by which tumors and virus-infected cells can evade recognition by the T-cell receptor of cytolytic T cells,(17,18) and NK cells can thereby overcome this potential immunologic Achilles’ heel....
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