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n the last years, our knowledge of human NK cell biology has increased significantly. Several stimulating studies have provided the basis for understanding how NK cells can be “educated” to acquire immunological competence following maturation, or to adapt their function to the environmental changes of “self”. New information has been acquired on their lifespan and on the persistence of memory-like NK cell subsets in response to certain viral infections. In addition, the identification and characterization of new markers and the development of more effective analytic approaches have led to the definition of various phenotypically and/or functionally-defined cell subsets. These advances have, in turn, enabled us to study NK cells beyond the peripheral blood, in different tissue compartments including the bone marrow, liver, lungs, skin, intestine and uterus. Recent data indicates that at least part of the tissue NK cell compartment consists of resident cells (which rarely recirculate) characterized by tissue-specific phenotypes and, in some cases, endowed with specialized functions related to the distinct organs in which they reside. These findings stimulate further questions (i) on the origins of these putative tissue-specific NK cell subsets; (ii) on their functional interplay with the local microenvironment; (iii) on their immunological competence and memory capacity and (iv) on their possible specific functional role in healthy and diseased tissues. In this context, the assessment of phenotype, function, maturation, education, differentiation and reprogramming of effector functions in tissue NK cells represents a new stimulating field of investigation that would help to get a more comprehensive picture of NK cell biology. In this Research Topic, we collect articles that highlight the recent advances in our understanding of tissue NK cells and that provide insight into opening new viewpoints on the role of NK cells in both health and disease.

Medicine --- Immunology --- conventional NK cells --- tissue resident NK cells --- innate lymphoid cells --- tissue microenvironment --- NK receptors

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n the last years, our knowledge of human NK cell biology has increased significantly. Several stimulating studies have provided the basis for understanding how NK cells can be “educated” to acquire immunological competence following maturation, or to adapt their function to the environmental changes of “self”. New information has been acquired on their lifespan and on the persistence of memory-like NK cell subsets in response to certain viral infections. In addition, the identification and characterization of new markers and the development of more effective analytic approaches have led to the definition of various phenotypically and/or functionally-defined cell subsets. These advances have, in turn, enabled us to study NK cells beyond the peripheral blood, in different tissue compartments including the bone marrow, liver, lungs, skin, intestine and uterus. Recent data indicates that at least part of the tissue NK cell compartment consists of resident cells (which rarely recirculate) characterized by tissue-specific phenotypes and, in some cases, endowed with specialized functions related to the distinct organs in which they reside. These findings stimulate further questions (i) on the origins of these putative tissue-specific NK cell subsets; (ii) on their functional interplay with the local microenvironment; (iii) on their immunological competence and memory capacity and (iv) on their possible specific functional role in healthy and diseased tissues. In this context, the assessment of phenotype, function, maturation, education, differentiation and reprogramming of effector functions in tissue NK cells represents a new stimulating field of investigation that would help to get a more comprehensive picture of NK cell biology. In this Research Topic, we collect articles that highlight the recent advances in our understanding of tissue NK cells and that provide insight into opening new viewpoints on the role of NK cells in both health and disease.

conventional NK cells --- tissue resident NK cells --- innate lymphoid cells --- tissue microenvironment --- NK receptors

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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 --- 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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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 cell --- adoptive cell immunotherapy --- off-the-shelf NK cells --- ovarian cancer --- pediatric tumors --- checkpoint inhibitors --- NK cell metabolism

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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