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      Killer Ig-Like Receptors (KIRs): Their Role in NK Cell Modulation and Developments Leading to Their Clinical Exploitation

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          Abstract

          Natural killer (NK) cells contribute to the first line of defense against viruses and to the control of tumor growth and metastasis spread. The discovery of HLA class I specific inhibitory receptors, primarily of killer Ig-like receptors (KIRs), and of activating receptors has been fundamental to unravel NK cell function and the molecular mechanisms of tumor cell killing. Stemmed from the seminal discoveries in early ‘90s, in which Alessandro Moretta was the major actor, an extraordinary amount of research on KIR specificity, genetics, polymorphism, and repertoire has followed. These basic notions on NK cells and their receptors have been successfully translated to clinical applications, primarily to the haploidentical hematopoietic stem cell transplantation to cure otherwise fatal leukemia in patients with no HLA compatible donors. The finding that NK cells may express the PD-1 inhibitory checkpoint, particularly in cancer patients, may allow understanding how anti-PD-1 therapy could function also in case of HLA class I neg tumors, usually susceptible to NK-mediated killing. This, together with the synergy of therapeutic anti-checkpoint monoclonal antibodies, including those directed against NKG2A or KIRs, emerging in recent or ongoing studies, opened new solid perspectives in cancer therapy.

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          Most cited references175

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          HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.

          The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules. Here we report the identification of ligands for HLA-E. We constructed tetramers in which recombinant HLA-E and beta2-microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to phycoerythrin-labelled Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK-cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.
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            Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells

            Summary Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.
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              In search of the ‘missing self’: MHC molecules and NK cell recognition

              Immunology Today, 11, 237-244

                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                28 May 2019
                2019
                : 10
                : 1179
                Affiliations
                [1] 1Laboratory of Immunology, Department of Integrated Oncological Therapies, IRCCS Ospedale Policlinico San Martino , Genoa, Italy
                [2] 2Laboratory of Clinical and Experimental Immunology, Integrated Department of Services and Laboratories, IRCCS Istituto G. Gaslini , Genoa, Italy
                [3] 3Department of Experimental Medicine (DIMES), Center of Excellence for Biomedical Research, Università di Genova , Genoa, Italy
                [4] 4Department of Experimental Medicine (DIMES), Università di Genova , Genoa, Italy
                [5] 5Department of Pathology, IRCCS Sacro Cuore Don Calabria Hospital , Negrar, Italy
                [6] 6Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics Stanford School of Medicine , Stanford, CA, United States
                [7] 7Department of Laboratory Medicine, IRCCS Sacro Cuore Don Calabria Hospital , Negrar, Italy
                [8] 8Core Facilities, Integrated Department of Services and Laboratories, IRCCS Istituto G. Gaslini , Genoa, Italy
                [9] 9Department of Oncohematology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù , Rome, Italy
                [10] 10Laboratory of Tumor Immunology, Department of Immunology, IRCCS Ospedale Pediatrico Bambino Gesù , Rome, Italy
                Author notes

                Edited by: Eric Vivier, INSERM U1104 Centre d'Immunologie de Marseille-Luminy, France

                Reviewed by: Hans-Gustaf Ljunggren, Karolinska Institute (KI), Sweden; Salim Iqbal Khakoo, University of Southampton, United Kingdom

                *Correspondence: Lorenzo Moretta lorenzo.moretta@ 123456opbg.net

                This article was submitted to NK and Innate Lymphoid Cell Biology, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2019.01179
                6558367
                31231370
                71c0925e-e79e-49b1-9936-c6f122860215
                Copyright © 2019 Pende, Falco, Vitale, Cantoni, Vitale, Munari, Bertaina, Moretta, Del Zotto, Pietra, Mingari, Locatelli and Moretta.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 24 March 2019
                : 09 May 2019
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 206, Pages: 18, Words: 16783
                Funding
                Funded by: Associazione Italiana per la Ricerca sul Cancro 10.13039/501100005010
                Categories
                Immunology
                Review

                Immunology
                hla class i,killer immunoglobulin-like receptors,kir ligands,inhibitory checkpoints,nk alloreactivity,nk cell education,polymorphism

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