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Nature Feb 2024Natural killer (NK) cells are lymphocytes of the innate immune system. A key feature of NK cells is their ability to recognize a wide range of cells in distress,... (Review)
Review
Natural killer (NK) cells are lymphocytes of the innate immune system. A key feature of NK cells is their ability to recognize a wide range of cells in distress, particularly tumour cells and cells infected with viruses. They combine both direct effector functions against their cellular targets and participate in the generation, shaping and maintenance of a multicellular immune response. As our understanding has deepened, several therapeutic strategies focused on NK cells have been conceived and are currently in various stages of development, from preclinical investigations to clinical trials. Here we explore in detail the complexity of NK cell biology in humans and highlight the role of these cells in cancer immunity. We also analyse the harnessing of NK cell immunity through immune checkpoint inhibitors, NK cell engagers, and infusions of preactivated or genetically modified, autologous or allogeneic NK cell products.
Topics: Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Neoplasms; Immunity, Innate
PubMed: 38383621
DOI: 10.1038/s41586-023-06945-1 -
Nature Reviews. Immunology May 2019Natural killer (NK) cells are lymphocytes with important roles in innate and adaptive immune responses to tumours and viral infection. However, in certain chronic... (Review)
Review
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.
Topics: Animals; Chronic Disease; Humans; Killer Cells, Natural; Signal Transduction
PubMed: 30808985
DOI: 10.1038/s41577-019-0139-2 -
Molecular Cancer Aug 2020The tumor microenvironment is highly complex, and immune escape is currently considered an important hallmark of cancer, largely contributing to tumor progression and... (Review)
Review
The tumor microenvironment is highly complex, and immune escape is currently considered an important hallmark of cancer, largely contributing to tumor progression and metastasis. Named for their capability of killing target cells autonomously, natural killer (NK) cells serve as the main effector cells toward cancer in innate immunity and are highly heterogeneous in the microenvironment. Most current treatment options harnessing the tumor microenvironment focus on T cell-immunity, either by promoting activating signals or suppressing inhibitory ones. The limited success achieved by T cell immunotherapy highlights the importance of developing new-generation immunotherapeutics, for example utilizing previously ignored NK cells. Although tumors also evolve to resist NK cell-induced cytotoxicity, cytokine supplement, blockade of suppressive molecules and genetic engineering of NK cells may overcome such resistance with great promise in both solid and hematological malignancies. In this review, we summarized the fundamental characteristics and recent advances of NK cells within tumor immunometabolic microenvironment, and discussed potential application and limitations of emerging NK cell-based therapeutic strategies in the era of presicion medicine.
Topics: Animals; Biomarkers; Disease Management; Disease Progression; Disease Susceptibility; Energy Metabolism; Humans; Immunity, Innate; Immunomodulation; Immunotherapy; Killer Cells, Natural; Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 32762681
DOI: 10.1186/s12943-020-01238-x -
Journal of Hematology & Oncology Dec 2020Despite considerable progress has been achieved in the treatment of acute myeloid leukemia over the past decades, relapse remains a major problem. Novel therapeutic... (Review)
Review
Despite considerable progress has been achieved in the treatment of acute myeloid leukemia over the past decades, relapse remains a major problem. Novel therapeutic options aimed at attaining minimal residual disease-negative complete remission are expected to reduce the incidence of relapse and prolong survival. Natural killer cell-based immunotherapy is put forward as an option to tackle the unmet clinical needs. There have been an increasing number of therapeutic dimensions ranging from adoptive NK cell transfer, chimeric antigen receptor-modified NK cells, antibodies, cytokines to immunomodulatory drugs. In this review, we will summarize different forms of NK cell-based immunotherapy for AML based on preclinical investigations and clinical trials.
Topics: Animals; Antineoplastic Agents, Immunological; Cytokines; Humans; Immunologic Factors; Immunotherapy; Immunotherapy, Adoptive; Killer Cells, Natural; Leukemia, Myeloid, Acute; Receptors, Chimeric Antigen
PubMed: 33287858
DOI: 10.1186/s13045-020-00996-x -
Frontiers in Immunology 2021Natural killer (NK) cells are critical components of host innate immunity and function as the first line of defense against tumors and viral infection. There is... (Review)
Review
Natural killer (NK) cells are critical components of host innate immunity and function as the first line of defense against tumors and viral infection. There is increasing evidence that extracellular vesicles (EVs) are involved in the antitumor activity of NK cells. NK cell-derived EVs (NKEVs) carrying cargo such as cytotoxic proteins, microRNAs, and cytokines employ multiple mechanisms to kill tumor cells, but also exhibit immunomodulatory activity by stimulating other immune cells. Several studies have reported that NKEVs can reverse immune suppression under tolerogenic conditions and contribute to NK-mediated immune surveillance against tumors. Thus, NKEVs are a promising tool for cancer immunotherapy. In this review, we describe the biological effects and potential applications of NKEVs in antitumor immunity.
Topics: Animals; Biological Transport; Biomarkers; Cell Communication; Cytokines; Cytotoxicity, Immunologic; Extracellular Vesicles; Gene Expression Regulation, Neoplastic; Humans; Immunity, Innate; Immunomodulation; Immunotherapy; Killer Cells, Natural; Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 34093547
DOI: 10.3389/fimmu.2021.658698 -
Clinical Immunology (Orlando, Fla.) Apr 2017Natural killer (NK) cells are innate immune cytotoxic effector cells well known for their role in antiviral immunity and tumor immunosurveillance. In parts, this... (Review)
Review
Natural killer (NK) cells are innate immune cytotoxic effector cells well known for their role in antiviral immunity and tumor immunosurveillance. In parts, this knowledge stems from rare inherited immunodeficiency disorders in humans that abrogate NK cell function leading to immune impairments, most notably associated with a high susceptibility to viral infections. Phenotypically, these disorders range from deficiencies selectively affecting NK cells to complex general immune defects that affect NK cells but also other immune cell subsets. Moreover, deficiencies may be associated with reduced NK cell numbers or rather impair specific NK cell effector functions. In recent years, genetic defects underlying the various NK cell deficiencies have been uncovered and have triggered investigative efforts to decipher the molecular mechanisms underlying these disorders. Here we review the associations between inherited human diseases and NK cell development as well as function, with a particular focus on defects in NK cell exocytosis and cytotoxicity. Furthermore we outline how reports of diverse genetic defects have shaped our understanding of NK cell biology.
Topics: Animals; Genetic Variation; Humans; Immunologic Deficiency Syndromes; Killer Cells, Natural
PubMed: 26592356
DOI: 10.1016/j.clim.2015.11.004 -
Clinical Immunology (Orlando, Fla.) Apr 2017Cell therapy is a promising alternative to harsh chemotherapy and radiation therapy for cancer. Natural killer (NK) cells in particular have great potential for direct... (Review)
Review
Cell therapy is a promising alternative to harsh chemotherapy and radiation therapy for cancer. Natural killer (NK) cells in particular have great potential for direct use in adoptive immunotherapy (AI) for cancer and to improve the graft-vs-leukemia (GVL) effect of hematopoietic stem cell transplants (HSCTs). NK cell number and function are associated with a strong GVL effect without inducing graft-versus-host disease in most settings. Clinical trials demonstrating the therapeutic role of NK cells in HSCT recipients or testing the safety and efficacy of AI with NK cells have been primarily directed at treating acute myeloid leukemia, although investigators have used NK cells for treatment of other hematological diseases, sarcomas, carcinomas, and brain tumors. Major challenges must be overcome in making NK cell-based therapy cost-effective, the most important being the need to collect or generate an adequate number of effector cells. In this review, we discuss protocols for isolation, expansion, and in vitro propagation of large quantities of functional NK cells that meet the criteria for clinical applications. Among the methods described are the use of bioreactors for scaling up production and expansion of NK cells in the presence of interleukins and feeder cells. We also discuss novel methodologies that optimize the generation of clinical grade NK-cell products for AI.
Topics: Animals; Cell Transplantation; Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Lymphocyte Subsets
PubMed: 26883680
DOI: 10.1016/j.clim.2016.02.003 -
The Journal of Allergy and Clinical... Sep 2013Natural killer (NK) cells are part of the innate immune defense against infection and cancer and are especially useful in combating certain viral pathogens. The utility... (Review)
Review
Natural killer (NK) cells are part of the innate immune defense against infection and cancer and are especially useful in combating certain viral pathogens. The utility of NK cells in human health has been underscored by a growing number of persons who are deficient in NK cells and/or their functions. This can be in the context of a broader genetically defined congenital immunodeficiency, of which there are more than 40 presently known to impair NK cells. However, the abnormality of NK cells in certain cases represents the majority immunologic defect. In aggregate, these conditions are termed NK cell deficiency. Recent advances have added clarity to this diagnosis and identified defects in 3 genes that can cause NK cell deficiency, as well as some of the underlying biology. Appropriate consideration of these diagnoses and patients raises the potential for rational therapeutic options and further innovation.
Topics: Disease Susceptibility; Humans; Immunologic Deficiency Syndromes; Killer Cells, Natural; Virus Diseases
PubMed: 23993353
DOI: 10.1016/j.jaci.2013.07.020 -
Cancer Immunology Research Nov 2019Natural killer (NK) cells are critical effector lymphocytes mediating tumor immune surveillance and clearance. They do so by direct tumor killing using cytolytic... (Review)
Review
Natural killer (NK) cells are critical effector lymphocytes mediating tumor immune surveillance and clearance. They do so by direct tumor killing using cytolytic granules and death receptors, and by interfacing with and potentiating adaptive immune responses through the production of cytokines. From a therapeutic perspective, NK cells have been shown to exert graft-versus-leukemia activity in the context of hematopoietic stem cell transplantation and are important in the clinical efficacy of antibodies. Advances in basic and translational NK cell biology have led to multiple potential strategies to augment their activity to improve antitumor responses. Despite their potent effects, NK cells have been shown to be safe for adoptive cell therapy in both the autologous and allogeneic settings, with promising, but so far limited, clinical efficacy. This review will provide an overview of strategies being pursued to improve NK cell activity and efficacy, focusing on cell source, NK cell activation, and persistence.
Topics: Animals; Cell Survival; Cytokines; Humans; Immunotherapy, Adoptive; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Lymphocyte Activation; Neoplasms; Tumor Microenvironment
PubMed: 31676567
DOI: 10.1158/2326-6066.CIR-19-0404 -
Annual Review of Immunology Apr 2020The continuous interactions between host and pathogens during their coevolution have shaped both the immune system and the countermeasures used by pathogens. Natural... (Review)
Review
The continuous interactions between host and pathogens during their coevolution have shaped both the immune system and the countermeasures used by pathogens. Natural killer (NK) cells are innate lymphocytes that are considered central players in the antiviral response. Not only do they express a variety of inhibitory and activating receptors to discriminate and eliminate target cells but they can also produce immunoregulatory cytokines to alert the immune system. Reciprocally, several unrelated viruses including cytomegalovirus, human immunodeficiency virus, influenza virus, and dengue virus have evolved a multitude of mechanisms to evade NK cell function, such as the targeting of pathways for NK cell receptors and their ligands, apoptosis, and cytokine-mediated signaling. The studies discussed in this article provide further insights into the antiviral function of NK cells and the pathways involved, their constituent proteins, and ways in which they could be manipulated for host benefit.
Topics: Animals; Biomarkers; Cytokines; Host-Pathogen Interactions; Humans; Immune Evasion; Killer Cells, Natural; Receptors, Natural Killer Cell; Signal Transduction; Virus Diseases; Viruses
PubMed: 32340578
DOI: 10.1146/annurev-immunol-082619-124440