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One-Year Follow-Up of Natural Killer Cell Activity in Multiple Myeloma One-Year Follow-Up of Natural Killer Cell Activity in Multiple Myeloma Patients Treated With Adjuvant Lenalidomide Therapy Laurie Besson, Emily Charrier, Lionel Karlin, Omran Allatif, Antoine Marçais, Paul Rouzaire, Lucie Belmont, Michel Attal, Christine Lombard, Gilles Salles, et al. To cite this version: Laurie Besson, Emily Charrier, Lionel Karlin, Omran Allatif, Antoine Marçais, et al.. One- Year Follow-Up of Natural Killer Cell Activity in Multiple Myeloma Patients Treated With Adjuvant Lenalidomide Therapy. Frontiers in Immunology, Frontiers, 2018, 9, pp.704. 10.3389/fimmu.2018.00704. hal-01833354 HAL Id: hal-01833354 https://hal.archives-ouvertes.fr/hal-01833354 Submitted on 22 Oct 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License ORIGINAL RESEARCH published: 13 April 2018 doi: 10.3389/fimmu.2018.00704 One-Year Follow-Up of Natural Killer Cell Activity in Multiple Myeloma Patients Treated With Adjuvant Lenalidomide Therapy Laurie Besson1,2,3,4,5,6†, Emily Charrier1,2,3,4,5,6†, Lionel Karlin7, Omran Allatif 1,2,3,4,5, Antoine Marçais1,2,3,4,5, Paul Rouzaire8, Lucie Belmont 6, Michel Attal 9, Christine Lombard6, Gilles Salles7, Thierry Walzer1,2,3,4,5† and Sébastien Viel1,2,3,4,5,6*† 1 CIRI, Centre International de Recherche en Infectiologie—International Center for Infectiology Research, Lyon, France, 2 INSERM, U1111, Lyon, France, 3 Ecole Normale Supérieure de Lyon, Lyon, France, 4 Université Lyon 1, Lyon, France, 5 CNRS, UMR5308, Lyon, France, 6 Laboratoire d’Immunologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France, 7 Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d’Hematologie, Pierre-Benite, Universite Claude Bernard Lyon 1, Lyon, France, 8 Service d’Immunologie, CHU de Clermont-Ferrand, équipe ERTICa EA4677, Université d’Auvergne, Clermont-Ferrand, France, 9 Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France Edited by: Multiple myeloma (MM) is a proliferation of tumoral plasma B cells that is still incurable. Marina Cella, Natural killer (NK) cells can recognize and kill MM cells in vitro and can limit MM growth Washington University in St. Louis, United States in vivo. Previous reports have shown that NK cell function is impaired during MM pro- Reviewed by: gression and suggested that treatment with immunomodulatory drugs (IMIDs) such as Evelyn Ullrich, lenalidomide (LEN) could enhance it. However, the effects of IMIDs on NK cells have been Goethe University Frankfurt, tested mostly in vitro or in preclinical models and supporting evidence of their effect in vivo Germany Alessandra Zingoni, in patients is lacking. Here, we monitored NK cell activity in blood samples from 10 MM Sapienza Università patients starting after frontline induction chemotherapy (CTX) consisting either of asso- di Roma, Italy ciation of bortezomib–lenalidomide–dexamethasone (Velcade Revlimid Dexamethasone) *Correspondence: Sébastien Viel or autologous stem-cell transplantation (SCT). We also monitored NK cell activity lon- [email protected] gitudinally each month during 1 year, after maintenance therapy with LEN. Following †These authors have contributed frontline chemotherapy, peripheral NK cells displayed a very immature phenotype and equally to this work. retained poor reactivity toward target cells ex vivo. Upon maintenance treatment with LEN, we observed a progressive normalization of NK cell maturation, likely caused by Specialty section: This article was submitted discontinuation of chemotherapy. However, LEN treatment neither activated NK cells nor to NK and Innate improved their capacity to degranulate or to secrete IFN-γ or MIP1-β following stimulation Lymphoid Cell Biology, a section of the journal with MHC-I-deficient or antibody-coated target cells. Upon LEN discontinuation, there Frontiers in Immunology was no reduction of NK cell effector function either. These results caution against the use Received: 15 January 2018 of LEN as single therapy to improve NK cell activity in patients with cancer and call for Accepted: 22 March 2018 more preclinical assessments of the potential of IMIDs in NK cell activation. Published: 13 April 2018 Citation: Keywords: natural killer cells, lenalidomide, immunomodulatory drugs, immunomonitoring, innate immunity, Besson L, Charrier E, Karlin L, multiple myeloma Allatif O, Marçais A, Rouzaire P, Belmont L, Attal M, Lombard C, INTRODUCTION Salles G, Walzer T and Viel S (2018) One-Year Follow-Up of Natural Killer Multiple myeloma (MM) is a genetically heterogeneous disease characterized by a proliferation of Cell Activity in Multiple Myeloma Patients Treated With Adjuvant tumoral plasma B cells (1). MM is among the most frequent hematologic malignancies and induces Lenalidomide Therapy. anemia, bone lesions, and renal dysfunction. Despite the emergence of several novel dedicated thera- Front. Immunol. 9:704. pies, MM remains of poor prognosis, because most patients become refractory to treatments (2). doi: 10.3389/fimmu.2018.00704 MM frequently progresses from a premalignant stage called monoclonal gammopathy of undetermined Frontiers in Immunology | www.frontiersin.org 1 April 2018 | Volume 9 | Article 704 Besson et al. Impact of LEN on NK Cells significance. Upon diagnosis, patients present either smoldering LEN on NKT cells in a small number of patients (17). Another (or indolent) asymptomatic MM or symptomatic MM with organ one reported weak signs of NK cell activation 1 month after the damages that require immediate treatment. Efforts are underway beginning of LEN as maintenance therapy, but the interpretation to understand genetic and other factors that influence progres- of the results was complicated by the prior allogenic stem-cell sion of indolent to active MM and to find treatments that could transplantation (SCT) of all patients and the discontinuation of prevent or delay this progression (1). immunosuppressive therapy used to reduce GVHD at the time Cytotoxic lymphocytes such as natural killer (NK), and of LEN treatment (18). Thus, a stimulatory effect of LEN on CD8 T cells are important actors of tumor immune surveil- NK cell activity in human in vivo remains to be formally proven. lance. NK cells mediate various antitumor functions, including To address this point, we monitored NK cells in patients with MM granule-dependent cytotoxicity, secretion of cytokines like treated only with LEN as maintenance chemotherapy. TNF-α and IFN-γ, as well as secretion of CCL3-5 chemokines, that have distinct roles during immune responses (3). NK cells MATERIALS AND METHODS recognize tumor cells through an arsenal of activating or inhibi- tory receptors. They can also recognize and kill antibody-coated Patients and Samples target cells through CD16, the low-affinity activating receptor for Patients were recruited in the context of the IFM/DFCI 2009 trial the Fc fragment of immunoglobulins G. This process is called (#NCT01191060) and followed in the Hospital Lyon Sud. Patients antibody dependent cell-mediated cytotoxicity (ADCC) (4) under 65 years old with newly diagnosed symptomatic MM were and is supposed to be one of the mechanisms of action of many randomized to receive, after frontline induction regimen with therapeutic monoclonal antibodies (5). three cycles of bortezomib–lenalidomide–dexamethasone (VRD Natural killer cells have long been shown to recognize and kill for Velcade/Revlimid/Dexamethasone), either SCT conditioned MM cells in vitro. HLA and activating receptors such as NKG2D, with high dose of Melphalan, followed by a two-cycle VRD DNAM1, and NKp46 are important for the recognition of MM consolidation, or five additional VRD cycles without high dose cells by NK cells (6–8). However, as for many tumors, other therapy. The two arms then received 1 year maintenance with sin- articles have suggested a gradual alteration of peripheral NK cell gle agent LEN. Patients’ characteristics are summarized in Table 1 activity during MM progression [reviewed in Ref. (9)]. and results of the clinical trial were recently published (19). Lenalidomide (LEN) is part of the immunomodulatory drugs The clinical trial protocol was initially approved by the insti- (iMIDs) and is a synthetic derivative of thalidomide currently tutional ethics committee at the coordinating center (Purpan approved by regulatory agencies for the treatment of MM, in Hospital, Toulouse, France). For our study, patients provided combination with dexamethasone. LEN presumably targets the an additional written informed consent in accordance with the ubiquitin ligase Cereblon (CRBN), and CRBN is required for Declaration of Helsinki. LEN antitumor function (10). The mechanisms of LEN actions Blood of age- and sex-matched healthy volunteers came from in MM include direct antitumor effects, effects on tumor stroma blood donors of the Etablissement Français du Sang Rhône-Alpes, and angiogenesis, and a positive effect on the antitumor immune who had given their written informed consent according
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