title: Human NK cells: From surface receptors to clinical applications.
abstract: Natural killer (NK) cells play a major role in innate defenses against pathogens, primarily viruses, and are also thought to be part of the immunosurveillance against tumors. They express an array of surface receptors that mediate NK cell function. The human leukocytes antigen (HLA) class I-specific inhibitory receptors allow NK cells to detect and kill cells that have lost or under-express HLA class I antigens, a typical feature of tumor or virally infected cells. However, NK cell activation and induction of cytolytic activity and cytokine production depends on another important checkpoint, namely the expression on target cells of ligands recognized by activating NK receptors. Despite their potent cytolytic activity, NK cells frequently fail to eliminate tumors. This is due to mechanisms of tumor escape, determined by the tumor cells themselves or by tumor-associated cells (i.e. the tumor microenvironment) via the release of soluble suppressive factors or the induction of inhibitory loops involving induction of regulatory T cells, M2-polarized macrophages and myeloid-derived suppressor cells. The most important clinical application involving NK cells is the cure of high-risk leukemias in the haplo-identical hematopoietic stem cell transplant (HSCT) setting. NK cells originated from hematopoietic stem cells (HSC) of HLA-haploidentical donors may express Killer Immunoglobulin-like receptors (KIRs) that are mismatched with the HLA class I alleles of the recipient. This allows NK cells to kill leukemia blasts residual after the conditioning regimen, while sparing normal cells (that do not express ligands for activating NK receptors). More recent approaches based on the specific removal of TCR α/β(+) T cells and of CD19(+) B cells, allow the infusion, together with CD34(+) HSC, of mature KIR(+) NK cells and of TCR γ/δ(+) T cells, both characterized by a potent anti-leukemia activity. This greatly reduces the time interval necessary to obtain alloreactive, KIR(+) NK cells derived from donor HSC. Another promising approach is based on the use of anti-KIR blocking monoclonal antibodies (mAbs), rendering alloreactive any KIR(+) NK cells.
authors.affiliation: Department of Immunology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy. Electronic address: lorenzo.moretta@opbg.net.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy; U.O. Immunology IRCCS AOU San Martino-IST, Genova, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pietra
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Vacca
authors.affiliation: U.O. Immunology IRCCS AOU San Martino-IST, Genova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pende
authors.affiliation: Department of Internal Medicine, University of Verona, Verona, Italy; Ospedale Sacro Cuore Negrar, Verona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Moretta
authors.affiliation: Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bertaina
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy; U.O. Immunology IRCCS AOU San Martino-IST, Genova, Italy; Centro di Eccellenza per la Ricerca Biomedica-CEBR, Genova, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mingari
authors.affiliation: Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy; Department of Pediatrics, University of Pavia, Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy; Centro di Eccellenza per la Ricerca Biomedica-CEBR, Genova, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
mesh_terms: D018380:Hematopoietic Stem Cell Transplantation; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D055607:Receptors, Natural Killer Cell / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; D055607:Receptors, Natural Killer Cell
keywords: Hematopoietic stem cell transplantation (HSCT); Innate lymphoid cells (ILC); NK cells; Tumor microenvironment