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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 -
Cell Mar 2020NK cells are broadly distributed innate lymphoid cells (ILCs) encompassing distinct populations based on CD11b and CD27 expression in mice or CD56 intensity in humans....
NK cells are broadly distributed innate lymphoid cells (ILCs) encompassing distinct populations based on CD11b and CD27 expression in mice or CD56 intensity in humans. Involved in anti-viral and anti-tumor immunity thanks to their cytokines and chemokines secretion as well as their cytotoxic capabilities, NK cells have emerged as a promising therapeutic target in several solid tumors and hematological malignancies. To view this Snapshot, open or download the PDF.
Topics: Animals; Cytokines; Humans; Immunity, Innate; Immunotherapy, Active; Killer Cells, Natural; Mice; Neoplasms
PubMed: 32200803
DOI: 10.1016/j.cell.2020.02.029 -
The Journal of Clinical Investigation Sep 2019Natural killer (NK) cells are innate cytotoxic lymphocytes involved in the surveillance and elimination of cancer. As we have learned more and more about the mechanisms... (Review)
Review
Natural killer (NK) cells are innate cytotoxic lymphocytes involved in the surveillance and elimination of cancer. As we have learned more and more about the mechanisms NK cells employ to recognize and eliminate tumor cells, and how, in turn, cancer evades NK cell responses, we have gained a clear appreciation that NK cells can be harnessed in cancer immunotherapy. Here, we review the evidence for NK cells' critical role in combating transformed and malignant cells, and how cancer immunotherapies potentiate NK cell responses for therapeutic purposes. We highlight cutting-edge immunotherapeutic strategies in preclinical and clinical development such as adoptive NK cell transfer, chimeric antigen receptor-expressing NK cells (CAR-NKs), bispecific and trispecific killer cell engagers (BiKEs and TriKEs), checkpoint blockade, and oncolytic virotherapy. Further, we describe the challenges that NK cells face (e.g., postsurgical dysfunction) that must be overcome by these therapeutic modalities to achieve cancer clearance.
Topics: Animals; Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Neoplasms
PubMed: 31478911
DOI: 10.1172/JCI129338 -
Mediators of Inflammation 2020Natural killer cells (NK cells) play an important role in innate immunity. NK cells recognize self and nonself depending on the balance of activating receptors and... (Review)
Review
Natural killer cells (NK cells) play an important role in innate immunity. NK cells recognize self and nonself depending on the balance of activating receptors and inhibitory receptors. After binding to their ligands, NK cell receptors trigger subsequent signaling conduction and then determine whether NK is activated or inhibited. Furthermore, NK cell response includes cytotoxicity and cytokine release, which is tightly related to the activation of NK cell-activating receptors and the inhibition of inhibitory receptors on the surfaces of NK cells. The expression and function of NK cell surface receptors also alter in virus infection, tumor, and autoimmune diseases and influence the occurrence and development of diseases. So, it is important to understand the mechanism of recognition between NK receptors and their ligands in pathological conditions and the signaling pathways of NK cell receptors. This review mainly summarizes the research progress on NK cell surface receptors and their signal pathways.
Topics: Animals; Humans; Immunity, Innate; Killer Cells, Natural; Receptors, Natural Killer Cell; Signal Transduction
PubMed: 32774149
DOI: 10.1155/2020/6437057 -
Frontiers in Immunology 2023
Topics: Antiviral Agents; Killer Cells, Natural; Immunity, Innate
PubMed: 36999011
DOI: 10.3389/fimmu.2023.1175111 -
Frontiers in Immunology 2021Chimeric antigen receptors (CARs) are fusion proteins with an extracellular antigen recognition domain and numerous intracellular signaling domains that have been... (Review)
Review
Chimeric antigen receptors (CARs) are fusion proteins with an extracellular antigen recognition domain and numerous intracellular signaling domains that have been genetically modified. CAR-engineered T lymphocyte-based therapies have shown great success against blood cancers; however, potential fatal toxicity, such as in cytokine release syndrome, and high costs are some shortcomings that limit the clinical application of CAR-engineered T lymphocytes and remain to overcome. Natural killer (NK) cells are the focal point of current immunological research owing to their receptors that prove to be promising immunotherapeutic candidates for treating cancer. However, to date, manipulation of NK cells to treat malignancies has been moderately successful. Recent progress in the biology of NK cell receptors has greatly transformed our understanding of how NK cells recognize and kill tumor and infected cells. CAR-NK cells may serve as an alternative candidate for retargeting cancer because of their unique recognition mechanisms, powerful cytotoxic effects especially on cancer cells in both CAR-dependent and CAR-independent manners and clinical safety. Moreover, NK cells can serve as an 'off-the-shelf product' because NK cells from allogeneic sources can also be used in immunotherapies owing to their reduced risk of alloreactivity. Although ongoing fundamental research is in the beginning stages, this review provides an overview of recent developments implemented to design CAR constructs to stimulate NK activation and manipulate NK receptors for improving the efficiency of immunotherapy against cancer, summarizes the preclinical and clinical advances of CAR-NK cells against both hematological malignancies and solid tumors and confronts current challenges and obstacles of their applications. In addition, this review provides insights into prospective novel approaches that further enhance the efficiency of CAR-NK therapies and highlights potential questions that require to be addressed in the future.
Topics: Antibody-Dependent Cell Cytotoxicity; Apoptosis; Clinical Trials as Topic; Cytokines; Cytotoxicity, Immunologic; Drug Design; Fas Ligand Protein; Forecasting; GPI-Linked Proteins; HLA Antigens; Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Lentivirus; Ligands; Macrophages; NK Cell Lectin-Like Receptor Subfamily K; Neoplasms; Receptors, Chimeric Antigen; Receptors, IgG; Receptors, Natural Killer Cell; Self Tolerance; T-Lymphocyte Subsets; Transduction, Genetic; Tumor Microenvironment; fas Receptor
PubMed: 34970253
DOI: 10.3389/fimmu.2021.707542 -
Cytometry. Part a : the Journal of the... Aug 2013Natural killer (NK) cells are important components of the innate immunity and play a key role in host defense by virtue of their ability to release cytokines and to... (Review)
Review
Natural killer (NK) cells are important components of the innate immunity and play a key role in host defense by virtue of their ability to release cytokines and to mediate cytolytic activity against tumor cells and virus-infected cells. NK cells were first described more than 30 years ago on the basis of their peculiar functional capabilities. Subsequently, thanks to the production of a variety of monoclonal antibodies, it became possible to identify surface receptors and markers expressed by NK cells as well as to characterize their functional properties. Here, we provide a brief historical overview about the discovery of human NK cell receptors and we delineate the main phenotypic features of differentiating and mature NK cells in healthy donors as well as their alterations in certain pathologic conditions.
Topics: Animals; Antigens, CD; Biomarkers; Cell Differentiation; Cytomegalovirus Infections; HIV Infections; Hepatitis C; Humans; Killer Cells, Natural; Phenotype; Receptors, Immunologic
PubMed: 23650273
DOI: 10.1002/cyto.a.22302 -
Immunology Jul 2018Natural killer (NK) cells express an array of germ-line encoded receptors that are capable of triggering cytotoxicity. NK cells tend to express many members of a given... (Review)
Review
Natural killer (NK) cells express an array of germ-line encoded receptors that are capable of triggering cytotoxicity. NK cells tend to express many members of a given family of signalling molecules. The presence of many activating receptors and many members of a given family of signalling molecules can enable NK cells to detect different kinds of target cells, and to mount different kinds of responses. This contributes also to the robustness of NK cells responses; cytotoxic functions of NK cells often remain unaffected in the absence of selected signalling molecules. NK cells express many MHC-I-specific inhibitory receptors. Signals from MHC-I-specific inhibitory receptors tightly control NK cell cytotoxicity and, paradoxically, maintain NK cells in a state of proper responsiveness. This review provides a brief overview of the events that underlie NK cell activation, and how signals from inhibitory receptors intercept NK cell activation to prevent inappropriate triggering of cytotoxicity.
Topics: Animals; Costimulatory and Inhibitory T-Cell Receptors; Cytotoxicity, Immunologic; Histocompatibility Antigens; Humans; Immunological Synapses; Immunomodulation; Killer Cells, Natural; Lymphocyte Activation; Signal Transduction
PubMed: 29512837
DOI: 10.1111/imm.12921 -
Cancer Journal (Sudbury, Mass.)Natural killer (NK) cells possess an innate ability to recognize cancer and are key mediators of cytotoxic efficacy for anticancer antibodies. Recent advances in the...
Natural killer (NK) cells possess an innate ability to recognize cancer and are key mediators of cytotoxic efficacy for anticancer antibodies. Recent advances in the ability to generate, qualify, and safely infuse NK cells have led to a wide variety of clinical trials in oncology. Although their efficacy is best established for liquid cancers, their potential application in solid cancers has received increased attention. Here, we provide general background across a disparate group of exemplary solid tumors for which there is evidence for an NK cell role, discuss NK cell recognition motifs specific to each and murine and human studies of each that are supportive of NK cell adoptive immunotherapy, and end with special considerations relevant to the solid tumor microenvironment.
Topics: Animals; Antineoplastic Agents; Humans; Immunotherapy; Immunotherapy, Adoptive; Killer Cells, Natural; Mice; Neoplasms; Tumor Microenvironment
PubMed: 35880935
DOI: 10.1097/PPO.0000000000000610 -
Methods in Molecular Biology (Clifton,... 2010Natural killer (NK) cells are a subset of lymphocytes that contribute to innate immunity through cytokine secretion and target cell lysis. NK cell function is regulated...
Natural killer (NK) cells are a subset of lymphocytes that contribute to innate immunity through cytokine secretion and target cell lysis. NK cell function is regulated by a multiplicity of activating and inhibitory receptors. The advance in instrumentation for multi-color flow cytometry and the generation of specific mAbs for different epitopes related to phenotypic and functional parameters have facilitated our understanding of NK cell responses. Here, we provide protocols for flow cytometric evaluation of degranulation and cytokine production by human NK cells from peripheral blood at the single-cell level. In addition to offering insight into the regulation of human NK cell responses, these techniques are applicable to the assessment of various clinical conditions, including the diagnosis of immunodeficiency syndromes.
Topics: Animals; Cell Degranulation; Cell Line; Cytokines; Flow Cytometry; Humans; Killer Cells, Natural; Time Factors
PubMed: 20033652
DOI: 10.1007/978-1-60761-362-6_23