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Recognition and killing of aberrant, infected or tumor targets by Natural Killer (NK) cells is mediated by positive signals transduced by activating receptors upon engagement of ligands on target surface. These stimulatory pathways are counterbalanced by inhibitory receptors that raise NK cell activation threshold through negative antagonist signals. While regulatory effects are necessary for physiologic control of autoimmune aggression, they may restrain the ability of NK cells to activate against disease. Overcoming this barrier to immune surveillance, multiple approaches to enhance NK-mediated responses are being investigated since two decades. Propelled by considerable advances in the understanding of NK cell biology, these studies are critical for effective translation of NK-based immunotherapy principles into the clinic. In humans, dominant inhibitory signals are transduced by Killer Immunoglobulin Like Receptors (KIR) recognizing cognate HLA class I on target cells. Conversely, KIR recognition of “missing self-HLA” - due to HLA loss or HLA/ KIR mismatch - triggers NK-mediated tumor rejection. Initially observed in murine transplant models, these antitumor effects were later found to have important implications for the clinical outcome of haplotype-mismatched stemcell transplantation. Here, donor NK subsets protect against acute myeloid leukemia (AML) relapse through missing self recognition of donor HLA-C allele groups (C1 or C2) and/or Bw4 epitope. These studies were subsequently extended by trials investigating the antileukemia effects of adoptively transferred haplotype-mismatched NK cells in non-transplant settings. Other mechanisms have been found to induce clinically relevant NK cell alloreactivity in transplantation, e.g., post-reconstitution functional reversal of anergic NK cells. More recently, activating KIR came into the spotlight for their potential ability to directly activate donor NK cells through in vivo recognition of HLA or other ligands. Novel therapeutic monoclonal antibodies (mAb) may optimize NK-mediated effects. Examples include obinutuzumab (GA101), a glyco-engineered anti-CD20 mAb with increased affinity for the FcγRIIIA receptor, enhancing antibody-dependent cellular cytotoxicity; lirilumab (IPH2102), a first-in-class NK-specific checkpoint inhibitor, blocking the interaction between the major KIR and cognate HLA-C antigens; and elotuzumab (HuLuc63), a humanized monoclonal antibody specific for SLAMF7, whose anti-myeloma therapeutic effects are partly due to direct activation of SLAMF7-expressing NK cells. In addition to conventional antibodies, NK cell-targeted bispecific (BiKEs) and trispecific (TriKEs) killer engagers have also been developed. These proteins elicit potent effector functions by binding target ligands (e.g., CD19, CD22, CD30, CD133, HLA class II, EGFR) on one arm and NK receptors on the other. An additional innovative approach to direct NK cell activity is genetic reprogramming with chimeric antigen receptors (CAR). To date, primary NK cells and the NK92 cell line have been engineered with CAR specific for antigens expressed on multiple tumors. Encouraging preclinical results warrant further development of this approach. This Research Topic welcomes contributions addressing mechanisms of NK-mediated activation in response to disease as well as past and contemporary strategies to enhance NK mediated reactivity through control of the interactions between NK receptors and their ligands.

Chimeric antigen receptors --- Checkpoint inhibitors --- NK receptors --- Immunotherapy --- Transplantation --- Natural killer cells --- Immune evasion --- Cancer --- Bispecific antibodies --- Chimeric antigen receptors --- Checkpoint inhibitors --- NK receptors --- Immunotherapy --- Transplantation --- Natural killer cells --- Immune evasion --- Cancer --- Bispecific antibodies

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The book Natural Killer Cells is the result of a collective work that addresses in a clear and comprehensive way for readers and through as many sensuous details as possible, the most and various fundamental aspects of natural killer cells, as well as their clinical applications in cancer immunotherapy. This book will serve as an invaluable resource and pedagogical support for clinicians, researchers, basic scientists, immunology and immunopathology lecturers, as well as for students in biology and medicine, especially the ones with an advanced understanding of immunology.

Killer cells. --- K cells --- Natural killer cells --- NK cells --- Immunocompetent cells --- Cell-mediated cytotoxicity --- Life Sciences --- Immunology and Microbiology --- Cancer Immunology --- Pure Immunology

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Medicine --- Immunology --- cellular therapy --- chimeric antigen receptor-T cell therapy --- chimeric antigen receptor-natural killer cell therapy --- adoptive cell therapy --- T cells --- natural killer cells --- immune effector cells --- cancer --- cellular therapy --- chimeric antigen receptor-T cell therapy --- chimeric antigen receptor-natural killer cell therapy --- adoptive cell therapy --- T cells --- natural killer cells --- immune effector cells --- cancer

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The existence of a unique kind of immune cell – the killer lymphocyt- which destroys other cells in a highly specific manner, has fascinated immunologists for almost half a century. How do these cells, whose precursors have lived in communal harmony with their host, decide that some of their cohabitants must die? And how do they kill them? The definition of killer lymphocytes came from discovery of their roles in a wide range of in vivo phenomena such as transplant rejection, virus infection and its related immunopathologies, and anti-tumor responses. Yet for the most part almost everything we know about these cells has come from studying them in vitro. They have yielded their secrets slowly and reluctantly. To understand fully how they work, geneticists and immunologists had to unravel the major histocompatibility systems of vertebrates, a long and torturous road that provided some of the darkest hours of immunology. The search for antigen-sensing receptors on both T cells and NK cells was scarcely less frustrating. And the holy grail of ce- mediated cytotoxicity – defining the mechanism by which killer cells take down their adversaries – sorely tested the ingenuity, patience and mutual good will of laboratories around the world. These questions have now largely been answered. But do we really understand these cells? We can tame them to a large degree in transplant rejection. It may yet turn out that we can harness their immunotherapeutic potential in treating viral and malignant disease.

Killer cells. --- Lymphocytes. --- Nongranular leucocytes --- Leucocytes --- K cells --- Natural killer cells --- NK cells --- Immunocompetent cells --- Cell-mediated cytotoxicity --- Immunologie --- Lymfocyten --- Immunology. --- Oncology. --- Medical virology. --- Microbiology. --- Bacteriology. --- Hematology. --- Cancer Research. --- Virology. --- Haematology --- Internal medicine --- Blood --- Microbiology --- Microbial biology --- Biology --- Microorganisms --- Medical microbiology --- Virology --- Virus diseases --- Tumors --- Immunobiology --- Life sciences --- Serology --- Diseases --- Cancer research. --- Cancer research

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To celebrate the 40th anniversary of the discovery of Natural Killer (NK) cells, this volume focuses on the recent advances in our understanding of NK cell development and differentiation and their acquisition of functional properties, as well as the latest models for NK-cell analysis in mice and applications in clinical medicine. NK cells have travelled a circuitous path from their initial description as ‘spontaneous killers’ (for some simply an experimental artifact) to being a bona fide subset of innate lymphoid cells with a complementary mode of action in immune defense and an important mediator of immune reactivity in health and disease. Together, these reviews provide a timely and concise picture of the evolution of NK cells as essential agents in immunity and as potent weapons against disease. This book offers an appealing and insightful resource for scientists and clinicians.

Microbiology & Immunology --- Biology --- Health & Biological Sciences --- Killer cells. --- Cell-mediated cytotoxicity. --- Cytotoxicity, Cell-mediated --- K cells --- Natural killer cells --- NK cells --- Cell death --- Killer cells --- Immunocompetent cells --- Cell-mediated cytotoxicity --- Immunology. --- Medical virology. --- Oncology. --- Virology. --- Cancer Research. --- Tumors --- Medical microbiology --- Virology --- Virus diseases --- Immunobiology --- Life sciences --- Serology --- Cancer research. --- Cancer research --- Microbiology