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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

NK cells --- NK cell-based immunotherapy --- cancer immunotherapy --- immune checkpoint inhibitors --- adoptive transfer of NK and CAR-NK cells --- ligands for NK cell-activating receptors

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Natural killer (NK) cells are innate lymphoid cells that have a significant role in regulating the defenses against cancer development and certain viral infections. They are equipped with an array of activating and inhibitory receptors that stimulate or diminish NK cell activity, respectively. Inhibitory receptors include, among others, the MHC class I ligands killer cell immunoglobulin-like receptors (KIR) in humans, and members of the Ly49 family of receptors in mice, and CD94/NKG2A. Activating receptors include cytokine and chemokine receptors, and those that interact with ligands expressed on target cells, such as the natural cytotoxicity receptors or NCRs (NKp30, NKp44 and NKp46), NKG2D, CD244 and DNAM-1. In addition, NK cells express Fc?RIIIA or CD16, the receptor that exerts antibody-dependent cell mediated cytotoxicity (ADCC). NK cells also express the death ligands FasL and TRAIL. The killing or sparing of target cells depends on the integration of distinct signals that originate from NK cell receptors. NK cells spare healthy cells that express normal levels of MHC class I molecules and low amounts of stress-induced self-molecules, whereas they kill target cells that down-regulate MHC class I molecules and/or up-regulate stress-induced self-molecules. The latter are common signatures of virus-infected cells and tumors. All the accumulated knowledge on NK cell biology, along with many clinical observations, is driving multiple efforts to improve the arsenal of NK cell-based therapeutic tools in the fight against malignant diseases. Indeed, NK cell-based immunotherapy is becoming a promising approach for the treatment of many cancers. It is well known that NK cells have a significant role in the anti-tumor effect of therapeutic antibodies that use ADCC as a mechanism of action. In addition to this, administration of autologous and allogeneic NK cells after activation and expansion ex vivo is used in the treatment of cancer. Moreover, adoptive transfer of NK cell lines has been tested in humans, and genetically modified NK cells expressing chimeric antigen receptors are being studied in preclinical models for potential use in the clinic.

NK cells --- Cytokines --- NK-92 --- CAR --- cancer immunotherapy --- adoptive cell therapy --- ADCC

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Natural Killer (NK) cells are innate lymphocytes, now recognized as members of a larger family of “Innate lymphoid cells” (ILCs). Both murine and human NK cells are well characterized effector cells with cytotoxic as well as cytokine production ability which mainly react in response to microbial and cell stress stimuli, thus playing a central role in the defense against pathogen infection, in tumor surveillance and in regulating immune homeostasis. Despite these established concepts, our understanding of the complexity of NK cells, also in view of their developmental and functional relationship with other ILC subsets, is only recently emerging. This Research Topic highlights the recent advances in NK cell (and ILC) research in human and mouse from basic research to clinical applications.

natural killer cells --- ILC --- NK cells --- immune therapy --- viral infection --- NK cell education --- immunotherapy --- MHC-I --- cancer --- immune regulation --- adaptive immunity

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Natural Killer (NK) cells were discovered ca 1975, as the first group of lymphoid cells that were neither T cells nor B cells. Since then, the dissection of the biology of NK cells has been growing exponentially with many seminal discoveries from the identification of MHC class I-specific inhibitory receptors to the discovery of receptor-ligand pairs involved in NK cell activation and to the manipulation of NK cells in cancer. In this research topic, we asked a group of thought leaders in NK cell biology to review recent advances in their origins and biology, and their roles in cancer, infection and inflammation. Together, these 25 articles provide a timely survey of NK cells as critical immunologic components of health and disease. They will hopefully prompt further dialogue and developments in basic and translational immunology.

ILCs --- inflammation --- NK cell subsets --- immunotherapy --- anti-viral responses --- anti-tumor responses --- immune checkpoints

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Cell-based immunotherapy is based on the seemingly simple principle of harnessing the power of the immune system to combat cancer, and is emerging as an important clinical tool. The remarkable success of CAR-T cell therapies demonstrate that cell based therapies are effective at eradicating hematological malignancies, and therefore hold great promise for other cancers. However, there are number of challenges that limit the full potential of cell based therapies, especially for solid cancers. T cells and NK cells represent major lymphocyte populations that are involved in immune surveillance and tumor eradication, and both are emerging as important players for cell based immunotherapy. Although they use different mechanisms for recognizing cancer cells, they complement each other during tumor eradication. NK cells have many functional similarities to T cells and represent the closest innate immune cell lineage to adaptive immune cell populations. Transcriptome analysis has also revealed similar phylogenetic origin of the two lymphocyte populations. The hurdles that impact therapeutic success of these cells include trafficking of lymphocytes to the tumor sites, recognition of solid tumors, and overcoming the inhospitable tumor microenvironment (TME) including the presence of suppressive cells (Treg and MDSC) and immune suppressive cytokines (TGFβ). The full potential of cell based therapies may be realized once tools to overcome these barriers are developed. This Research Topic collects articles critically examining these obstacles and the novel strategies being developed for cell-based therapies to overcome them.

immunotherapy --- NK cell --- tumor micoenvironment --- CAR (chimeric antigen receptor) T cells --- cell based therapy