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Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages

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Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages This information is current as Francesca Bellora, Alessandra Dondero, Maria Valeria of September 28, 2021. Corrias, Beatrice Casu, Stefano Regis, Fabio Caliendo, Alessandro Moretta, Mario Cazzola, Chiara Elena, Luciana Vinti, Franco Locatelli, Cristina Bottino and Roberta Castriconi J Immunol published online 12 July 2017 Downloaded from http://www.jimmunol.org/content/early/2017/07/12/jimmun ol.1601695 Supplementary http://www.jimmunol.org/content/suppl/2017/07/12/jimmunol.160169 http://www.jimmunol.org/ Material 5.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • 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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 12, 2017, doi:10.4049/jimmunol.1601695 The Journal of Immunology Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages Francesca Bellora,*,1 Alessandra Dondero,*,1 Maria Valeria Corrias,† Beatrice Casu,* Stefano Regis,† Fabio Caliendo,* Alessandro Moretta,*,‡ Mario Cazzola,x,{ Chiara Elena,x Luciana Vinti,‖ Franco Locatelli,x,‖ Cristina Bottino,*,†,2 and Roberta Castriconi*,‡,2 Tyrosine kinase inhibitors (TKIs) are used in the clinical management of hematological neoplasms. Moreover, in solid tumors such as stage 4 neuroblastomas (NB), imatinib showed benefits that might depend on both on-target and immunological off-target effects. We investigated the effects of imatinib and nilotinib on human NK cells, monocytes, and macrophages. High numbers of monocytes died upon exposure to TKI concentrations similar to those achieved in patients. Conversely, NK cells were highly resistant to the TKI Downloaded from cytotoxic effect, were properly activated by immunostimulatory cytokines, and degranulated in the presence of NB cells. In NB, neither drug reduced the expression of ligands for activating NK receptors or upregulated that of HLA class I, B7-H3, PD-L1, and PD-L2, molecules that might limit NK cell function. Interestingly, TKIs modulated the chemokine receptor repertoire of immune cells. Acting at the transcriptional level, they increased the surface expression of CXCR4, an effect observed also in NK cells and monocytes of patients receiving imatinib for chronic myeloid leukemia. Moreover, TKIs reduced the expression of CXCR3 (in NK cells) and CCR1 (in monocytes). Monocytes also decreased the expression of M-CSFR, and low numbers of cells underwent dif- http://www.jimmunol.org/ ferentiation toward macrophages. M0 and M2 macrophages were highly resistant to TKIs and maintained their phenotypic and functional characteristics. Importantly, also in the presence of TKIs, the M2 immunosuppressive polarization was reverted by TLR engagement, and M1-oriented macrophages fully activated autologous NK cells. Our results contribute to better interpreting the off- target efficacy of TKIs in tumors and to envisaging strategies aimed at facilitating antitumor immune responses. The Journal of Immunology, 2017, 199: 000–000. irtually all patients with chronic myeloid leukemia Imatinib mesylate (Glivec) was the first designed protein tyrosine (CML) and 20% of adult patients with acute lym- kinase inhibitor (TKI) used in the treatment of CML and BCR- by guest on September 28, 2021 V phoblastic leukemia carry the translocation between the ABL+ ALL (1–3). This drug binds to the protein in a fashion that long arms of chromosomes 9 and 22 that generates the Philadelphia prevents ATP interacting with the ATP-binding site of the ABL chromosome with a chimeric gene that encodes the fusion protein kinase, thereby blocking the tyrosine phosphorylation of proteins BCR-ABL, having constitutively activated tyrosine kinase activity. involved in BCR-ABL signal transduction (4). Importantly, in imatinib-resistant or intolerant BCR-ABL+ patients, an alternative therapy is based on the administration of nilotinib (Tasigna), a *Dipartimento di Medicina Sperimentale, Universita` degli Studi di Genova, 16132 Genoa, Italy; †Istituto Giannina Gaslini, 16148 Genoa, Italy; ‡Centro di Eccellenza second-generation TKI that, in vitro, is more potent and selective per la Ricerca Biomedica, Universita` degli Studi di Genova, 16132 Genoa, Italy; than imatinib as a BCR-ABL tyrosine kinase inhibitor (5–7). xDipartimento di Medicina Molecolare, Universita` di Pavia, 27100 Pavia, Italy; {Dipartimento di Onco-Ematologia, Fondazione Istituto di Ricovero e Cura a Carattere Imatinib and nilotinib also target the discoidin domain receptors 1 Scientifico Policlinico San Matteo, 27100 Pavia, Italy; and ‖Dipartimento di Onco- and 2, the platelet-derived growth factor receptors a and b (8), the Ematologia Pediatrica, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale M-CSF receptor (9), and KIT (stem cell growth factor receptor, Pediatrico Bambino Gesu`, 00146 Rome, Italy CD117) (10, 11). KIT is constitutively active in most human 1F.B. and A.D. contributed equally to this work. gastrointestinal stromal tumors (GISTs), a common mesenchymal 2 C.B. and R.C. share cosenior authorship of this work. neoplasm of the gastrointestinal tract and, in this context, imatinib ORCIDs: 0000-0002-1932-0608 (F.B.); 0000-0002-7316-0772 (M.V.C.); 0000-0002- is registered for the treatment of GISTs (12, 13). Neuroblastomas 5676-6000 (F.C.); 0000-0001-6984-8817 (M.C.); 0000-0001-6695-1739 (C.B.); 0000-0003-2806-1115 (R.C.). (NB) represent the most common extracranial solid malignancy of Received for publication October 3, 2016. Accepted for publication June 11, 2017. childhood (14); they frequently localize in the abdomen, particularly This work was supported by Associazione Italiana per la Ricerca sul Cancro Inves- in the adrenal gland or at lumbar sympathetic ganglia. Metastatic tigator Grant 15704 (to A.M.) and Special Program Molecular Clinical Oncology 5 disease (stage 4), very often characterized by bone marrow (BM) per 1000 Grant 9962 (to A.M. and F.L.). F.B. is the recipient of Associazione Italiana infiltration, is diagnosed in at least 50% of NB patients and it is still per la Ricerca sul Cancro Fellowship IG.15704. associated with a dismal prognosis because of a high risk of tumor Address correspondence and reprint requests to Prof. Alessandro Moretta, Dipartimento di Medicina Sperimentale, Universita` degli Studi di Genova, Via Leon Battista Alberti relapse. Children with either refractory or relapsing metastatic NB 2, 16132 Genoa, Italy. E-mail address: [email protected] have been recently enrolled in a two-stage, phase II clinical trial with The online version of this article contains supplemental material. imatinib; the drug was well tolerated and showed benefits in a subset Abbreviations used in this article: BM, bone marrow; CML, chronic myeloid leuke- of patients, particularly those with BM as the only site of metasta- mia; GIST, gastrointestinal stromal tumor; mIL-18, the membrane-bound form of tization, low tumor infiltration, and low imatinib exposure (15). IL-18; NB, neuroblastoma; PB, peripheral blood; TKI, tyrosine kinase inhibitor. It has been suggested that the efficacy of imatinib in GISTs might Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 depend on both on- and off-target effects, with the latter being www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601695 2 OFF-TARGET EFFECTS OF IMATINIB AND NILOTINIB related to the antiangiogenic effects and strengthening of antitumor In this study, we examined the effect of two TKIs, imatinib and immune responses (16–18). It is conceivable to speculate that also nilotinib, routinely used in the clinical management of several neo- in NB, the efficacy of imatinib might be at least in part related to plasms, on the survival and function of human NK cells, monocytes, the enhancement of the anti-NB activity of immune cells, such as and macrophages, also considering their polarization properties and NK cells. When properly activated, NK cells exert a potent cy- ability to interact with autologous NK cells. tolytic activity and release immunostimulatory cytokines such as IFN-g that potentiate both innate and adaptive immune responses, Materials and Methods thus representing important effectors against both hematological Cells and TKIs and nonhematological malignancies (19, 20). The NK cell activation depends on the interaction between Buffy coats were collected from healthy volunteer blood donors admitted at the blood transfusion center of IRCCS S. Martino-IST after obtaining activating NK receptors and their cognate ligands on tumor targets. informed consent, and the study was approved by the Ethics Commit- In humans, the principal activating receptors include NKp46, tee of IRCCS San Martino-IST (39/2012). After standard Ficoll-Paque NKp30, and NKp44 (collectively
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