{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T11:48:37Z","timestamp":1778932117804,"version":"3.51.4"},"reference-count":89,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,8,29]],"date-time":"2021-08-29T00:00:00Z","timestamp":1630195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health (Rome, Italy)","award":["GR-2011-02352151"],"award-info":[{"award-number":["GR-2011-02352151"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>High-risk neuroblastoma (NB) is a rare childhood cancer whose aggressiveness is due to a variety of chromosomal genetic aberrations, including those conferring immune evasion. Indeed, NB cells adopt several molecular strategies to evade recognition by the immune system, including the downregulation of ligands for NK-cell-activating receptors. To date, while molecular strategies aimed at enhancing the expression of ligands for NKG2D- and DNAM-1-activating receptors have been explored, no evidence has been reported on the immunomodulatory mechanisms acting on the expression of death receptors such as Fas in NB cells. Here, we demonstrated that transient overexpression of the NF-kB p65 subunit upregulates the surface expression of Fas and PVR, the ligand of DNAM-1, thus making NB cell lines significantly more susceptible to NK-cell-mediated apoptosis, recognition, and killing. In contrast, IFN\u03b3 and TNF\u03b1 treatment, although it induced the upregulation of FAS in NB cells and consequently enhanced NK-cell-mediated apoptosis, triggered immune evasion processes, including the strong upregulation of MHC class I and IDO1, both of which are involved in mechanisms leading to the impairment of a proper NK-cell-mediated killing of NB. In addition, high-resolution array CGH analysis performed in our cohort of NB patients revealed that the loss of FAS and\/or PVR genes correlated with low survival independently of the disease stage. Our data identify the status of the FAS and PVR genes as prognostic biomarkers of NB that may predict the efficacy of NK-cell-based immunotherapy of NB. Overall, restoration of surface expression of Fas and PVR, through transient upregulation of NF-kB, may be a clue to a novel NK-cell-based immunotherapy of NB.<\/jats:p>","DOI":"10.3390\/cancers13174368","type":"journal-article","created":{"date-parts":[[2021,8,29]],"date-time":"2021-08-29T21:45:16Z","timestamp":1630273516000},"page":"4368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome"],"prefix":"10.3390","volume":"13","author":[{"given":"Elisa","family":"Brandetti","sequence":"first","affiliation":[{"name":"Academic Department of Pediatrics (DPUO), Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7334-3966","authenticated-orcid":false,"given":"Chiara","family":"Focaccetti","sequence":"additional","affiliation":[{"name":"Department of Human Science and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy"},{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Pezzolo","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3698-9319","authenticated-orcid":false,"given":"Marzia","family":"Ognibene","sequence":"additional","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Folgiero","sequence":"additional","affiliation":[{"name":"Department of Paediatric Haematology\/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Cotugno","sequence":"additional","affiliation":[{"name":"Research Unit of Clinical Immunology and Vaccinology, DPUO, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2520-1306","authenticated-orcid":false,"given":"Monica","family":"Benvenuto","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"},{"name":"Saint Camillus International University of Health and Medical Sciences, 00131 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3066-4719","authenticated-orcid":false,"given":"Paolo","family":"Palma","sequence":"additional","affiliation":[{"name":"Research Unit of Clinical Immunology and Vaccinology, DPUO, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vittorio","family":"Manzari","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Rossi","sequence":"additional","affiliation":[{"name":"Academic Department of Pediatrics (DPUO), Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3388-7296","authenticated-orcid":false,"given":"Doriana","family":"Fruci","sequence":"additional","affiliation":[{"name":"Department of Paediatric Haematology\/Oncology and of Cell and Gene Therapy, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9541-8896","authenticated-orcid":false,"given":"Roberto","family":"Bei","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5014-430X","authenticated-orcid":false,"given":"Loredana","family":"Cifaldi","sequence":"additional","affiliation":[{"name":"Academic Department of Pediatrics (DPUO), Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00165 Rome, Italy"},{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16078","DOI":"10.1038\/nrdp.2016.78","article-title":"Neuroblastoma","volume":"2","author":"Matthay","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/B978-0-12-800267-4.00003-1","article-title":"Recognition of tumors by the innate immune system and natural killer cells","volume":"122","author":"Marcus","year":"2014","journal-title":"Adv. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-019-0052-1","article-title":"NK cells for cancer immunotherapy","volume":"19","author":"Shimasaki","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"873","DOI":"10.3389\/fimmu.2020.00873","article-title":"Enhancing Neuroblastoma Immunotherapies by Engaging iNKT and NK Cells","volume":"11","author":"McNerney","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sordo-Bahamonde, C., Lorenzo-Herrero, S., Payer, A.R., Gonzalez, S., and Lopez-Soto, A. (2020). Mechanisms of Apoptosis Resistance to NK Cell-Mediated Cytotoxicity in Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103726"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1056\/NEJMra0804577","article-title":"Recent advances in neuroblastoma","volume":"362","author":"Maris","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.canlet.2004.11.064","article-title":"Mechanisms of immune evasion of human neuroblastoma","volume":"228","author":"Raffaghello","year":"2005","journal-title":"Cancer Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1316439","DOI":"10.1080\/2162402X.2017.1316439","article-title":"MYCN is an immunosuppressive oncogene dampening the expression of ligands for NK-cell-activating receptors in human high-risk neuroblastoma","volume":"6","author":"Brandetti","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5998","DOI":"10.1158\/0008-5472.CAN-10-3211","article-title":"Human NK cells are alerted to induction of p53 in cancer cells by upregulation of the NKG2D ligands ULBP1 and ULBP2","volume":"71","author":"Textor","year":"2011","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1158\/2326-6066.CIR-20-0313","article-title":"Nutlin-3a Enhances Natural Killer Cell-Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors","volume":"9","author":"Veneziani","year":"2021","journal-title":"Cancer Immunol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1084\/jem.20030788","article-title":"Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule","volume":"198","author":"Bottino","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1093\/intimm\/dxh059","article-title":"Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2\/CD112)","volume":"16","author":"Shibuya","year":"2004","journal-title":"Int. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1084\/jem.20150792","article-title":"DNAM-1 controls NK cell activation via an ITT-like motif","volume":"212","author":"Zhang","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4972410","DOI":"10.1155\/2018\/4972410","article-title":"Neuroblastoma Cell Lines Are Refractory to Genotoxic Drug-Mediated Induction of Ligands for NK Cell-Activating Receptors","volume":"2018","author":"Veneziani","year":"2018","journal-title":"J. Immunol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.18632\/oncotarget.26736","article-title":"The BET-bromodomain inhibitor JQ1 renders neuroblastoma cells more resistant to NK cell-mediated recognition and killing by downregulating ligands for NKG2D and DNAM-1 receptors","volume":"10","author":"Veneziani","year":"2019","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1126\/science.7533326","article-title":"The Fas death factor","volume":"267","author":"Nagata","year":"1995","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2276","DOI":"10.1073\/pnas.1218295110","article-title":"Fas expression by tumor stroma is required for cancer eradication","volume":"110","author":"Listopad","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/cdd.2015.3","article-title":"The role of CD95 and CD95 ligand in cancer","volume":"22","author":"Peter","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_19","first-page":"4864","article-title":"Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2","volume":"61","author":"Poulaki","year":"2001","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"403","DOI":"10.3389\/fimmu.2017.00403","article-title":"Dual Role of Fas\/FasL-Mediated Signal in Peripheral Immune Tolerance","volume":"8","author":"Yamada","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.humimm.2004.01.004","article-title":"Regulation of FasL expression in natural killer cells","volume":"65","author":"Chua","year":"2004","journal-title":"Hum. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1006\/cyto.1996.0181","article-title":"Regulation of Fas and Fas-ligand expression in NK cells by cytokines and the involvement of Fas-ligand in NK\/LAK cell-mediated cytotoxicity","volume":"9","author":"Medvedev","year":"1997","journal-title":"Cytokine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/cdd.2011.155","article-title":"Regulation of CD95\/Fas signaling at the DISC","volume":"19","author":"Lavrik","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e212","DOI":"10.1038\/cddis.2011.93","article-title":"Caspase-8 activity has an essential role in CD95\/Fas-mediated MAPK activation","volume":"2","author":"Kober","year":"2011","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1158\/1055-9965.EPI-10-0030","article-title":"FAS and FASLG genetic variants and risk for second primary malignancy in patients with squamous cell carcinoma of the head and neck","volume":"19","author":"Lei","year":"2010","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1158\/1078-0432.CCR-08-0177","article-title":"Functional variants in cell death pathway genes and risk of pancreatic cancer","volume":"14","author":"Yang","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s00439-009-0639-4","article-title":"FAS -1,377 G\/A polymorphism is associated with cancer susceptibility: Evidence from 10,564 cases and 12,075 controls","volume":"125","author":"Qiu","year":"2009","journal-title":"Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1182\/blood-2011-04-349803","article-title":"A functional variant in the core promoter of the CD95 cell death receptor gene predicts prognosis in acute promyelocytic leukemia","volume":"119","author":"Sunter","year":"2012","journal-title":"Blood"},{"key":"ref_29","first-page":"4327","article-title":"Functional FAS promoter polymorphisms are associated with increased risk of acute myeloid leukemia","volume":"63","author":"Sibley","year":"2003","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/sj.cdd.4401190","article-title":"Autoimmune lymphoproliferative syndromes: Genetic defects of apoptosis pathways","volume":"10","author":"Fischer","year":"2003","journal-title":"Cell Death Differ."},{"key":"ref_31","first-page":"5","article-title":"Fas and Fas ligand interactions in malignant disease","volume":"17","author":"Chan","year":"2000","journal-title":"Int. J. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S1097-2765(01)00199-X","article-title":"Cooperation between STAT3 and c-jun suppresses Fas transcription","volume":"7","author":"Ivanov","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_33","first-page":"4638","article-title":"p53 promotes selection for Fas-mediated apoptotic resistance","volume":"60","author":"Maecker","year":"2000","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.4049\/jimmunol.167.4.2068","article-title":"A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells","volume":"167","author":"Screpanti","year":"2001","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ccell.2017.06.009","article-title":"Control of Metastasis by NK Cells","volume":"32","author":"Gonzalez","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1128\/MCB.19.3.2098","article-title":"Activation-dependent transcriptional regulation of the human Fas promoter requires NF-kappaB p50-p65 recruitment","volume":"19","author":"Chan","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"25530","DOI":"10.1074\/jbc.M112.356279","article-title":"NF-kappaB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression","volume":"287","author":"Liu","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nature04870","article-title":"Nuclear factor-kappaB in cancer development and progression","volume":"441","author":"Karin","year":"2006","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"11093","DOI":"10.1158\/0008-5472.CAN-07-1576","article-title":"Nuclear factor-kappaB, an unappreciated tumor suppressor","volume":"67","author":"Chen","year":"2007","journal-title":"Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.ccr.2007.08.029","article-title":"Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis","volume":"12","author":"Petersen","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1101\/gad.17276711","article-title":"Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity","volume":"25","author":"Chien","year":"2011","journal-title":"Genes Dev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1038\/onc.2011.333","article-title":"Identification of a novel pro-apoptotic role of NF-kappaB in the regulation of TRAIL- and CD95-mediated apoptosis of glioblastoma cells","volume":"31","author":"Jennewein","year":"2012","journal-title":"Oncogene"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4909","DOI":"10.1158\/0008-5472.CAN-04-4124","article-title":"Apoptosis induction by a novel retinoid-related molecule requires nuclear factor-kappaB activation","volume":"65","author":"Farhana","year":"2005","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6354","DOI":"10.1158\/0008-5472.CAN-04-4061","article-title":"Activation of nuclear factor-kappaB contributes to induction of death receptors and apoptosis by the synthetic retinoid CD437 in DU145 human prostate cancer cells","volume":"65","author":"Jin","year":"2005","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/1476-4598-9-182","article-title":"NF-kappaB activation enhances cell death by antimitotic drugs in human prostate cancer cells","volume":"9","author":"Parrondo","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Mekhloufi, A., Kosta, A., Stabile, H., Molfetta, R., Zingoni, A., Soriani, A., Cippitelli, M., Paolini, R., Gismondi, A., and Ricciardi, M.R. (2020). Bone Marrow Stromal Cell-Derived IL-8 Upregulates PVR Expression on Multiple Myeloma Cells via NF-kB Transcription Factor. Cancers, 12.","DOI":"10.3390\/cancers12020440"},{"key":"ref_47","first-page":"2832","article-title":"IFN-gamma induces cell growth inhibition by Fas-mediated apoptosis: Requirement of STAT1 protein for up-regulation of Fas and FasL expression","volume":"58","author":"Xu","year":"1998","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4398","DOI":"10.1002\/(SICI)1521-4141(199812)28:12<4398::AID-IMMU4398>3.0.CO;2-Y","article-title":"TNF-alpha and IFN-gamma render microglia sensitive to Fas ligand-induced apoptosis by induction of Fas expression and down-regulation of Bcl-2 and Bcl-xL","volume":"28","author":"Spanaus","year":"1998","journal-title":"Eur. J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"743","DOI":"10.4049\/jimmunol.165.2.743","article-title":"TNF-alpha and IFN-gamma regulate expression and function of the Fas system in the seminiferous epithelium","volume":"165","author":"Riccioli","year":"2000","journal-title":"J. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/jid.2012.330","article-title":"TNF-alpha and IFN-gamma are potential inducers of Fas-mediated keratinocyte apoptosis through activation of inducible nitric oxide synthase in toxic epidermal necrolysis","volume":"133","author":"Gaide","year":"2013","journal-title":"J. Investig. Dermatol."},{"key":"ref_51","first-page":"311","article-title":"Interferon gamma and tumor necrosis factor alpha induce Fas expression and anti-Fas mediated apoptosis in a salivary ductal cell line","volume":"18","author":"Matsumura","year":"2000","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4126","DOI":"10.1242\/jcs.009761","article-title":"Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis","volume":"120","author":"Fluhr","year":"2007","journal-title":"J. Cell Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/sj.cdd.4401219","article-title":"TNF combined with IFN-alpha accelerates NF-kappaB-mediated apoptosis through enhancement of Fas expression in colon cancer cells","volume":"10","author":"Kimura","year":"2003","journal-title":"Cell Death Differ."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4949","DOI":"10.4049\/jimmunol.166.8.4949","article-title":"NF-kappa B RelA (p65) is essential for TNF-alpha-induced fas expression but dispensable for both TCR-induced expression and activation-induced cell death","volume":"166","author":"Zheng","year":"2001","journal-title":"J. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1158\/0008-5472.CAN-14-1643","article-title":"ERAP1 regulates natural killer cell function by controlling the engagement of inhibitory receptors","volume":"75","author":"Cifaldi","year":"2015","journal-title":"Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.1182\/blood-2008-06-164103","article-title":"Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: Evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity","volume":"113","author":"Pende","year":"2009","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/j.celrep.2017.06.084","article-title":"Identification of a Genetic Variation in ERAP1 Aminopeptidase that Prevents Human Cytomegalovirus miR-UL112-5p-Mediated Immunoevasion","volume":"20","author":"Romania","year":"2017","journal-title":"Cell Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1200\/JCO.1993.11.8.1466","article-title":"Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment","volume":"11","author":"Brodeur","year":"1993","journal-title":"J. Clin. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1002\/(SICI)1097-0142(19990715)86:2<364::AID-CNCR21>3.0.CO;2-7","article-title":"The International Neuroblastoma Pathology Classification (the Shimada system)","volume":"86","author":"Shimada","year":"1999","journal-title":"Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/sj.neo.7900146","article-title":"Detection of MYCN gene amplification in neuroblastoma by fluorescence in situ hybridization: A pediatric oncology group study","volume":"3","author":"Mathew","year":"2001","journal-title":"Neoplasia"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/bjc.2014.325","article-title":"Structurally diverse MDM2-p53 antagonists act as modulators of MDR-1 function in neuroblastoma","volume":"111","author":"Chen","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1158\/0008-5472.CAN-09-2582","article-title":"NF-kappaB, and not MYCN, regulates MHC class I and endoplasmic reticulum aminopeptidases in human neuroblastoma cells","volume":"70","author":"Forloni","year":"2010","journal-title":"Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Lorenzi, S., Forloni, M., Cifaldi, L., Antonucci, C., Citti, A., Boldrini, R., Pezzullo, M., Castellano, A., Russo, V., and van der Bruggen, P. (2012). IRF1 and NF-kB restore MHC class I-restricted tumor antigen processing and presentation to cytotoxic T cells in aggressive neuroblastoma. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046928"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5386","DOI":"10.1093\/emboj\/16.17.5386","article-title":"TRAIL-R2: A novel apoptosis-mediating receptor for TRAIL","volume":"16","author":"Walczak","year":"1997","journal-title":"EMBO J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/emm.1998.1","article-title":"Cytokine regulation of expression of class I MHC antigens","volume":"30","author":"Raval","year":"1998","journal-title":"Exp. Mol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.3389\/fimmu.2020.01185","article-title":"Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies","volume":"11","author":"Zhai","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Caforio, M., Sorino, C., Caruana, I., Weber, G., Camera, A., Cifaldi, L., De Angelis, B., Del Bufalo, F., Vitale, A., and Goffredo, B.M. (2021). GD2 redirected CAR T and activated NK-cell-mediated secretion of IFNgamma overcomes MYCN-dependent IDO1 inhibition, contributing to neuroblastoma cell immune escape. J. Immunother. Cancer, 9.","DOI":"10.1136\/jitc-2020-001502"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1080\/13543776.2018.1441290","article-title":"A patent review of IDO1 inhibitors for cancer","volume":"28","author":"Cheong","year":"2018","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1056\/NEJM199601253340405","article-title":"Expression of the gene for multidrug-resistance-associated protein and outcome in patients with neuroblastoma","volume":"334","author":"Norris","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.3389\/fimmu.2019.03038","article-title":"Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors","volume":"10","author":"Melaiu","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1111\/j.1582-4934.2011.01343.x","article-title":"NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin","volume":"16","author":"Esser","year":"2012","journal-title":"J. Cell. Mol. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.1038\/s41598-020-59082-4","article-title":"\u2018\u2018UniCAR\u2019\u2019-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells","volume":"10","author":"Mitwasi","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"a014415","DOI":"10.1101\/cshperspect.a014415","article-title":"Neuroblastoma and MYCN","volume":"3","author":"Huang","year":"2013","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1593\/neo.04316","article-title":"Downregulation and\/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma","volume":"6","author":"Raffaghello","year":"2004","journal-title":"Neoplasia"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.cell.2010.08.031","article-title":"Natural killer cell education and tolerance","volume":"142","author":"Orr","year":"2010","journal-title":"Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"47163","DOI":"10.18632\/oncotarget.9980","article-title":"Fas ligand and lytic granule differentially control cytotoxic dynamics of natural killer cell against cancer target","volume":"7","author":"Zhu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.tcb.2013.07.006","article-title":"Evading apoptosis in cancer","volume":"23","author":"Fernald","year":"2013","journal-title":"Trends Cell Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/s41419-020-2399-y","article-title":"Life, death, and autophagy in cancer: NF-kappaB turns up everywhere","volume":"11","author":"Verzella","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrd2781","article-title":"Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls","volume":"8","author":"Baud","year":"2009","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-kappaB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nature02924","article-title":"NF-kappaB functions as a tumour promoter in inflammation-associated cancer","volume":"431","author":"Pikarsky","year":"2004","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/978-1-4419-6612-4_8","article-title":"New perspectives in TNF-R1-induced NF-kappaB signaling","volume":"691","author":"Gentle","year":"2011","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Cornel, A.M., Mimpen, I.L., and Nierkens, S. (2020). MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy. Cancers, 12.","DOI":"10.3390\/cancers12071760"},{"key":"ref_84","first-page":"15","article-title":"Targeted Cancer Therapy with Tumor Necrosis Factor-Alpha","volume":"2008","author":"Cai","year":"2008","journal-title":"Biochem. Insights"},{"key":"ref_85","first-page":"6157","article-title":"Retinoic acid induction of major histocompatibility complex class I genes in NTera-2 embryonal carcinoma cells involves induction of NF-kappa B (p50\u2212p65) and retinoic acid receptor beta-retinoid X receptor beta heterodimers","volume":"13","author":"Segars","year":"1993","journal-title":"Mol. Cell Biol."},{"key":"ref_86","first-page":"343","article-title":"All-trans-retinoic acid induces nuclear factor kappaB activation and matrix metalloproteinase-9 expression and enhances basement membrane invasivity of differentiation-resistant human SK-N-BE 9N neuroblastoma Cells","volume":"13","author":"Farina","year":"2002","journal-title":"Cell Growth Differ."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6945","DOI":"10.1038\/sj.onc.1208842","article-title":"Betulinic acid as new activator of NF-kappaB: Molecular mechanisms and implications for cancer therapy","volume":"24","author":"Kasperczyk","year":"2005","journal-title":"Oncogene"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"6621","DOI":"10.1158\/0008-5472.CAN-18-0545","article-title":"Nedd4-Binding Protein 1 and TNFAIP3-Interacting Protein 1 Control MHC-1 Display in Neuroblastoma","volume":"78","author":"Spel","year":"2018","journal-title":"Cancer Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"133","DOI":"10.4049\/immunohorizons.1700035","article-title":"Interleukin-17 signaling triggers degradation of the constitutive NF-kappaB inhibitor ABIN-1","volume":"1","author":"Cruz","year":"2017","journal-title":"Immunohorizons"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/17\/4368\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:54:55Z","timestamp":1760165695000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/17\/4368"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,29]]},"references-count":89,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["cancers13174368"],"URL":"https:\/\/doi.org\/10.3390\/cancers13174368","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,29]]}}}