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Loss of the Immune Checkpoint Cd85j/LILRB1 on Malignant Plasma Cells

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Loss of the Immune Checkpoint Cd85j/LILRB1 on Malignant Plasma Cells Loss of the Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma This information is current as of September 28, 2021. Ester Lozano, Tania Díaz, Mari-Pau Mena, Guillermo Suñe, Xavier Calvo, Marcos Calderón, Lorena Pérez-Amill, Vanina Rodríguez, Patricia Pérez-Galán, Gaël Roué, M. Teresa Cibeira, Laura Rosiñol, Ignacio Isola, Luis-Gerardo Rodríguez-Lobato, Beatriz Martin-Antonio, Joan Bladé and Carlos Fernández de Larrea Downloaded from J Immunol published online 12 March 2018 http://www.jimmunol.org/content/early/2018/03/11/jimmun ol.1701622 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2018/03/11/jimmunol.170162 Material 2.DCSupplemental Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 12, 2018, doi:10.4049/jimmunol.1701622 The Journal of Immunology Loss of the Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma Ester Lozano,*,† Tania Dı´az,*,† Mari-Pau Mena,*,† Guillermo Sun˜e,*,‡ Xavier Calvo,* Marcos Caldero´n,*,† Lorena Pe´rez-Amill,*,‡ Vanina Rodrı´guez,† Patricia Pe´rez-Gala´n,† Gae¨l Roue´,†,x M. Teresa Cibeira,* Laura Rosin˜ol,* Ignacio Isola,* Luis-Gerardo Rodrı´guez- Lobato,* Beatriz Martin-Antonio,*,‡ Joan Blade´,*,‡ and Carlos Ferna´ndez de Larrea*,†,‡ Mechanisms of immune regulation may control proliferation of aberrant plasma cells (PCs) in patients with monoclonal gamm- opathy of undetermined significance (MGUS) preventing progression to active multiple myeloma (MM). We hypothesized that Downloaded from CD85j (LILRB1), an inhibitory immune checkpoint for B cell function, may play a role in MM pathogenesis. In this study, we report that patients with active MM had significantly lower levels of CD85j and its ligand S100A9. Decreased CD85j expression could also be detected in the premalignant condition MGUS, suggesting that loss of CD85j may be an early event promoting tumor immune escape. To gain insight into the molecular mechanisms underlying CD85j functions, we next enforced expression of CD85j in human myeloma cell lines by lentiviral transduction. Interestingly, gene expression profiling of CD85j-overexpressing cells revealed a set of downregulated genes with crucial functions in MM pathogenesis. Furthermore, in vitro functional assays http://www.jimmunol.org/ demonstrated that CD85j overexpression increased susceptibility to T cell– and NK-mediated killing. Consistently, ligation of CD85j decreased the number of PCs from individuals with MGUS but not from patients with MM. In conclusion, downregulation of inhibitory immune checkpoints on malignant PCs may provide a novel mechanism of immune escape associated with myeloma pathogenesis. The Journal of Immunology, 2018, 200: 000–000. ultiple myeloma (MM) is a clonal B cell malignancy marrow (BM) cells and PCs may show aberrant expression of characterized by neoplastic proliferation of a plasma receptors such as CD56 and CD117 (c-Kit). However, the annual M cell (PC) clone. Malignant PCs produce monoclonal rate of malignant transformation from MGUS to MM is 1% (6), Igs, which usually results in organ or tissue impairment (1, 2). MM indicating that mechanisms of control may prevent proliferation of by guest on September 28, 2021 accounts for approximately 13% of hematologic cancers and its aberrant PCs. The molecular mechanisms that maintain the frequency is likely to increase in the near future as the population MGUS state and the mechanisms that trigger progression from ages (1, 3). MM remains incurable although the median survival MGUS to MM are poorly understood. has recently increased due to the introduction of autologous stem- Immune cells must be tightly regulated to mount a specific cell transplantation and the availability of new agents such as immune response while avoiding autoimmunity. One mechanism of thalidomide, lenalidomide, and bortezomib (4, 5). MM is usually immune regulation is the presence of inhibitory immune check- preceded by the asymptomatic condition monoclonal gammopathy points on the surface of immune cells. Immune checkpoints may of undetermined significance (MGUS). In the asymptomatic contain ITIM, which can recruit phosphatases and deliver inhib- MGUS, the frequency of PCs may be up to 10% of the bone itory signals into the cell (7). Upregulation of ligands for inhibitory *Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clı´nic, Au- cytometry data analysis; V.R., P.P.-G., and G.R. performed gene expression analysis; gust Pi i Sunyer Biomedical Research Institute, University of Barcelona, 08036 B.M.-A., L.P.-A., and G.S. provided reagents and helped with functional NK cyto- Barcelona, Spain; †Division of Hematology and Oncology, August Pi i Sunyer Bio- toxicity assays; M.T.C., L.R., I.I., L.-G.R.-L., J.B., and C.F.d.L. provided patient medical Research Institute, 08036 Barcelona, Spain; ‡Josep Carreras Leukaemia samples and clinical data, designed research, and wrote the manuscript; all authors Research Institute, University of Barcelona, 08036 Barcelona, Spain; and xLabora- reviewed and approved the manuscript. tory of Experimental Hematology, Department of Hematology, Vall d’Hebron Insti- The microarray data presented in this article have been submitted to the Gene Ex- tute of Oncology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain pression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/) under accession ORCIDs: 0000-0002-6307-9807 (E.L.); 0000-0001-7934-9130 (X.C.); 0000- number GSE89793. 0003-0245-2257 (G.R.); 0000-0001-5694-0921 (L.-G.R.-L.); 0000-0003-0612- Address correspondence and reprint requests to Dr. Carlos Ferna´ndez de Larrea, 2693 (B.M.-A.). Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clı´nic de Received for publication November 27, 2017. Accepted for publication February 13, Barcelona, Institut d’Investigacions Biome`diques August Pi i Sunyer, Villarroel, 2018. 170, 08036 Barcelona, Spain. E-mail address: [email protected] This work was supported in part by Grants RD12/0036/0046 and PI16/00423 from The online version of this article contains supplemental material. Instituto de Salud Carlos III (Ministerio de Economı´a y Competitividad, Cofinan- Abbreviations used in this article: BM, bone marrow; CR, complete remission; ciado por Fondo Europeo de Desarrollo Regional, Union Europea, Una Manera de DAVID, Database for Annotation, Visualization, and Integrated Discovery; MGUS, Hacer Europa). This work was partially funded by a Generalitat de Catalunya grant monoclonal gammopathy of undetermined significance; MM, multiple myeloma; PC, (2014SGR-552), the CERCA Programme/Generalitat de Catalunya, and a Josep plasma cell; PD-1, programmed cell death protein 1; VGPR, very good partial Carreras Leukaemia Research Institute grant (CEL029). C.F.d.L. was the recipient response. of an Institut d’Investigacions Biome`diques August Pi i Sunyer starting grant (II040060). Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 E.L. performed experiments, analyzed data, and wrote the manuscript; T.D., M.-P.M., and M.C. performed experiments and analyzed results; X.C. performed flow www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701622 2 LOSS OF CD85j IN MULTIPLE MYELOMA checkpoints on the surface of tumor cells is one escape mecha- BM mononuclear cells from patients with MGUS or MM were obtained + nism that cancer cells may develop to inhibit the host immune by density gradient centrifugation (Ficoll; Sigma-Aldrich). Fresh CD138 system (8, 9). Blockade of inhibitory immune checkpoints has PCs were isolated with anti-CD138 mAb-coated immunomagnetic beads (Miltenyi Biotec, San Diego, CA) using an AutoMacs cell sorter (Miltenyi been approved for the treatment of solid tumors and hematologic Biotec). RNA from PCs was isolated using Trizol reagent and total RNA malignancies (10–12). However, the roles of inhibitory immune was retrotranscribed using High Capacity cDNA Reverse Transcription kit checkpoints when immune cells become tumor cells remain un- (Thermo Fisher Scientific). TaqMan Universal PCR Master Mix and known. We hypothesized that inhibitory immune checkpoints on probes were from Thermo Fisher Scientific. Reactions were run on a 7900 Real-Time PCR System (Thermo Fisher Scientific). Values are represented the surface of PCs may play a role in maintaining immune control as the difference in cycle threshold values normalized to endogenous in the premalignant condition MGUS. Thus, loss of these mech- control b-glucuronidase for each sample as per the following formula: anisms may confer a selective advantage to the aberrant clone relative RNA expression = 22d cycle threshold.
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