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      Monalizumab: inhibiting the novel immune checkpoint NKG2A

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          Abstract

          The implementation of immune checkpoint inhibitors to the oncology clinic signified a new era in cancer treatment. After the first indication of melanoma, an increasing list of additional cancer types are now treated with immune system targeting antibodies to PD-1, PD-L1 and CTLA-4, alleviating inhibition signals on T cells. Recently, we published proof-of-concept results on a novel checkpoint inhibitor, NKG2A. This receptor is expressed on cytotoxic lymphocytes, including NK cells and subsets of activated CD8 + T cells. Blocking antibodies to NKG2A unleashed the reactivity of these effector cells resulting in tumor control in multiple mouse models and an early clinical trial. Monalizumab is inhibiting this checkpoint in human beings and future clinical trials will have to reveal its potency in combination with other cancer treatment options.

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          Most cited references49

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          NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control

          Summary Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Notably, tumor production of prostaglandin E2 (PGE2) leads to evasion of the NK cell-cDC1 axis in part by impairing NK cell viability and chemokine production, as well as by causing downregulation of chemokine receptor expression in cDC1. Our findings reveal a cellular and molecular checkpoint for intratumoral cDC1 recruitment that is targeted by tumor-derived PGE2 for immune evasion and that could be exploited for cancer therapy.
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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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                Author and article information

                Contributors
                T.van_Hall@lumc.nl
                Vivier@ciml.univ-mrs.fr
                Journal
                J Immunother Cancer
                J Immunother Cancer
                Journal for Immunotherapy of Cancer
                BioMed Central (London )
                2051-1426
                17 October 2019
                17 October 2019
                2019
                : 7
                : 263
                Affiliations
                [1 ]ISNI 0000000089452978, GRID grid.10419.3d, Department of Medical Oncology, , Oncode Institute, Leiden University Medical Center, ; 2333 ZA Leiden, the Netherlands
                [2 ]ISNI 0000 0004 0626 1500, GRID grid.463905.d, Innate Pharma Research Labs, Innate Pharma, ; Marseille, France
                [3 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Oncological Sciences, , Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, ; New York, NY 10029 USA
                [4 ]ISNI 0000 0004 0639 5277, GRID grid.417850.f, Aix Marseille Université, INSERM, CNRS, Centre d’Immunologie de Marseille-Luminy, ; Marseille, France
                [5 ]ISNI 0000 0001 0404 1115, GRID grid.411266.6, Service d’Immunologie, Marseille Immunopole, , Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, ; Marseille, France
                Article
                761
                10.1186/s40425-019-0761-3
                6798508
                31623687
                95aaf6d1-3dc6-4fd3-831a-2454bf49785f
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 31 May 2019
                : 26 September 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004622, KWF Kankerbestrijding;
                Award ID: 2014-7146
                Award ID: 2014-6696
                Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: TILC, 694502
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001665, Agence Nationale de la Recherche;
                Award ID: prioneer ANR-17-RHUS-0007
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004099, Ligue Contre le Cancer;
                Award ID: Equipe labellisee
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                cancer immunotherapy,cd8 t cells,nk cells,nkg2a,inhibitory immune receptor,hla-e/qa-1

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