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• W4220736375 abstract "Neuroblastoma (NB) is an enigmatic and deadliest pediatric cancer to treat. The major obstacles to the effective immunotherapy treatments in NB are defective immune cells and the immune evasion tactics deployed by the tumor cells and the stromal microenvironment. Nervous system development during embryonic and pediatric stages is critically mediated by non-coding RNAs such as micro RNAs (miR). Hence, we explored the role of miRs in anti-tumor immune response via a range of data-driven workflows and in vitro & in vivo experiments. Using the TARGET, NB patient dataset (n=249), we applied the robust bioinformatic workflows incorporating differential expression, co-expression, survival, heatmaps, and box plots. We initially demonstrated the role of miR-15a-5p (miR-15a) and miR-15b-5p (miR-15b) as tumor suppressors, followed by their negative association with stromal cell percentages and a statistically significant negative regulation of T and natural killer (NK) cell signature genes, especially CD274 (PD-L1) in stromal-low patient subsets. The NB phase-specific expression of the miR-15a/miR-15b-PD-L1 axis was further corroborated using the PDX (n=24) dataset. We demonstrated miR-15a/miR-15b mediated degradation of PD-L1 mRNA through its interaction with the 3'-untranslated region and the RNA-induced silencing complex using sequence-specific luciferase activity and Ago2 RNA immunoprecipitation assays. In addition, we established miR-15a/miR-15b induced CD8+T and NK cell activation and cytotoxicity against NB in vitro. Moreover, injection of murine cells expressing miR-15a reduced tumor size, tumor vasculature and enhanced the activation and infiltration of CD8+T and NK cells into the tumors in vivo. We further established that blocking the surface PD-L1 using an anti-PD-L1 antibody rescued miR-15a/miR-15b induced CD8+T and NK cell-mediated anti-tumor responses. These findings demonstrate that miR-15a and miR-15b induce an anti-tumor immune response by targeting PD-L1 in NB. Neuroblastoma (NB) is an enigmatic and deadliest pediatric cancer to treat. The major obstacles to the effective immunotherapy treatments in NB are defective immune cells and the immune evasion tactics deployed by the tumor cells and the stromal microenvironment. Nervous system development during embryonic and pediatric stages is critically mediated by non-coding RNAs such as micro RNAs (miR). Hence, we explored the role of miRs in anti-tumor immune response via a range of data-driven workflows and in vitro & in vivo experiments. Using the TARGET, NB patient dataset (n=249), we applied the robust bioinformatic workflows incorporating differential expression, co-expression, survival, heatmaps, and box plots. We initially demonstrated the role of miR-15a-5p (miR-15a) and miR-15b-5p (miR-15b) as tumor suppressors, followed by their negative association with stromal cell percentages and a statistically significant negative regulation of T and natural killer (NK) cell signature genes, especially CD274 (PD-L1) in stromal-low patient subsets. The NB phase-specific expression of the miR-15a/miR-15b-PD-L1 axis was further corroborated using the PDX (n=24) dataset. We demonstrated miR-15a/miR-15b mediated degradation of PD-L1 mRNA through its interaction with the 3'-untranslated region and the RNA-induced silencing complex using sequence-specific luciferase activity and Ago2 RNA immunoprecipitation assays. In addition, we established miR-15a/miR-15b induced CD8+T and NK cell activation and cytotoxicity against NB in vitro. Moreover, injection of murine cells expressing miR-15a reduced tumor size, tumor vasculature and enhanced the activation and infiltration of CD8+T and NK cells into the tumors in vivo. We further established that blocking the surface PD-L1 using an anti-PD-L1 antibody rescued miR-15a/miR-15b induced CD8+T and NK cell-mediated anti-tumor responses. These findings demonstrate that miR-15a and miR-15b induce an anti-tumor immune response by targeting PD-L1 in NB. IntroductionNeuroblastoma (NB) is the most common pediatric cancer affecting children younger than 5 years.1Siegel R.L. Miller K.D. Fuchs H.E. Jemal A. Cancer statistics, 2021.CA Cancer J. Clin. 2021; 71: 7-33https://doi.org/10.3322/caac.21654Crossref PubMed Scopus (7019) Google Scholar, 2Mahapatra S. Challagundla K.B. Cancer, Neuroblastoma. StatPearls, 2020Google Scholar, 3Prathipati A. Pathania A.S. Chaturvedi N.K. Gupta S.C. Byrareddy S.N. Coulter D.W. Challagundla K.B. SAP30, an Oncogenic Driver of Progression, Survival, and Drug Resistance in High-Risk Neuroblastoma.Mol. Ther. Nucleic Acids. 2022; https://doi.org/10.1016/j.omtn.2022.03.014Abstract Full Text PDF Google Scholar NB develops from immature nerve cells, most commonly in adrenal glands situated above the kidney. NB accounts for 15% of childhood cancer-related mortality, and approximately 50% of children treated for high-risk NB have more aggressive tumor relapse with less than 20% 5-year overall survival.4Mueller S. Matthay K.K. Neuroblastoma: biology and staging.Curr. Oncol. 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Neuroblastoma incidence and survival in European children (1978-1997): report from the automated childhood cancer information system project.Eur. J. Cancer. 2006; 42: 2081-2091https://doi.org/10.1016/j.ejca.2006.05.008Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar During embryogenesis, multipotent neural crest cells differentiate into multiple cell types, including sympathetic neurons, adrenal medullary cells, and modified postganglionic sympathetic neurons.8Yamamoto M. Yanai R. Arishima K. Study of migration of neural crest cells to adrenal medulla by three-dimensional reconstruction.J. Vet. Med. Sci. 2004; 66: 635-641https://doi.org/10.1292/jvms.66.635Crossref PubMed Scopus (15) Google Scholar,9Chung K.F. Sicard F. Vukicevic V. Hermann A. Storch A. Huttner W.B. Bornstein S.R. Ehrhart-Bornstein M. Isolation of neural crest derived chromaffin progenitors from adult adrenal medulla.Stem Cell. 2009; 27: 2602-2613https://doi.org/10.1002/stem.180Crossref PubMed Scopus (51) Google Scholar The deregulation of signaling pathways involved in the differentiation of neural crest cells leads to NB development in the sympathetic nervous system or medullar region of the adrenal glands. NBs are highly heterogeneous tumors consisting of various sub-cell types, and they display various genomic alterations, including MYCN amplification,10Huang M. Weiss W.A. Neuroblastoma and MYCN.Cold Spring Harb. Perspect. Med. 2013; 3: a014415https://doi.org/10.1101/cshperspect.a014415Crossref PubMed Scopus (361) Google Scholar different DNA ploidy patterns,11Kusafuka T. Fukuzawa M. Oue T. Yoneda A. Okada A. Satani M. DNA flow cytometric analysis of neuroblastoma: distinction of tetraploidy subset.J. Pediatr. Surg. 1994; 29: 543-547https://doi.org/10.1016/0022-3468(94)90087-6Abstract Full Text PDF PubMed Scopus (9) Google Scholar deletion in the short arm of chromosome 1,12Ritke M.K. Shah R. Valentine M. Douglass E.C. Tereba A. Molecular analysis of chromosome 1 abnormalities in neuroblastoma.Cytogenet. Cell Genet. 1989; 50: 84-90https://doi.org/10.1159/000132729Crossref PubMed Scopus (24) Google Scholar a gain of chromosome 17q,13Plantaz D. Mohapatra G. Matthay K.K. Pellarin M. Seeger R.C. Feuerstein B.G. Gain of chromosome 17 is the most frequent abnormality detected in neuroblastoma by comparative genomic hybridization.Am. J. Pathol. 1997; 150: 81-89PubMed Google Scholar and chromosome 11q deletion.14Mlakar V. Jurkovic Mlakar S. Lopez G. Maris J.M. Ansari M. Gumy-Pause F. 11q deletion in neuroblastoma: a review of biological and clinical implications.Mol. Cancer. 2017; 16: 114https://doi.org/10.1186/s12943-017-0686-8Crossref PubMed Scopus (62) Google Scholar These genomic alterations, along with International NB Staging System, stage histopathology and age are used to classify NB patients into risk groups.15Brisse H.J. McCarville M.B. Granata C. Krug K.B. Wootton-Gorges S.L. Kanegawa K. Giammarile F. Schmidt M. Shulkin B.L. Matthay K.K. et al.Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project.Radiology. 2011; 261: 243-257https://doi.org/10.1148/radiol.11101352Crossref PubMed Scopus (291) Google Scholar,16Davidoff A.M. Neuroblastoma.Semin. Pediatr. Surg. 2012; 21: 2-14https://doi.org/10.1053/j.sempedsurg.2011.10.009Crossref PubMed Scopus (141) Google Scholar The high-risk NB patients are challenging to treat and require high doses of chemotherapy and radiotherapy in the clinic.17Smith V. Foster J. High-risk neuroblastoma treatment review.Children (Basel). 2018; 5: 114https://doi.org/10.3390/children5090114Crossref Scopus (93) Google Scholar, 18Matthay K.K. Villablanca J.G. Seeger R.C. Stram D.O. Harris R.E. Ramsay N.K. Swift P. Shimada H. Black C.T. Brodeur G.M. et al.Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group.N. Engl. J. Med. 1999; 341: 1165-1173https://doi.org/10.1056/nejm199910143411601Crossref PubMed Scopus (0) Google Scholar, 19Coughlan D. Gianferante M. Lynch C.F. Stevens J.L. Harlan L.C. Treatment and survival of childhood neuroblastoma: evidence from a population-based study in the United States.Pediatr. Hematol. Oncol. 2017; 34: 320-330https://doi.org/10.1080/08880018.2017.1373315Crossref PubMed Scopus (46) Google Scholar The chances of tumor regression (>50%) and death rate (41.7% compared with 0% in low-risk and 5.2% in intermediate-risk patients) in high-risk patients are higher than in other groups.19Coughlan D. Gianferante M. Lynch C.F. Stevens J.L. Harlan L.C. Treatment and survival of childhood neuroblastoma: evidence from a population-based study in the United States.Pediatr. Hematol. Oncol. 2017; 34: 320-330https://doi.org/10.1080/08880018.2017.1373315Crossref PubMed Scopus (46) Google Scholar,20Herd F. Basta N.O. McNally R.J.Q. Tweddle D.A. A systematic review of re-induction chemotherapy for children with relapsed high-risk neuroblastoma.Eur. J. Cancer. 2019; 111: 50-58https://doi.org/10.1016/j.ejca.2018.12.032Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Moreover, the use of intense treatment regimens has significant adverse effects on patients’ quality of life.Several investigators have tried different therapeutic approaches like high-dose chemotherapy, surgery, radiation therapy, stem cell transplantation, retinoid therapy, and immunotherapy to improve clinical outcomes in aggressive high-risk NB patients.17Smith V. Foster J. High-risk neuroblastoma treatment review.Children (Basel). 2018; 5: 114https://doi.org/10.3390/children5090114Crossref Scopus (93) Google Scholar,19Coughlan D. Gianferante M. Lynch C.F. Stevens J.L. Harlan L.C. Treatment and survival of childhood neuroblastoma: evidence from a population-based study in the United States.Pediatr. Hematol. Oncol. 2017; 34: 320-330https://doi.org/10.1080/08880018.2017.1373315Crossref PubMed Scopus (46) Google Scholar,21Fischer J. Pohl A. Volland R. Hero B. Dubbers M. Cernaianu G. Berthold F. von Schweinitz D. Simon T. Complete surgical resection improves outcome in INRG high-risk patients with localized neuroblastoma older than 18 months.BMC Cancer. 2017; 17: 520https://doi.org/10.1186/s12885-017-3493-0Crossref PubMed Scopus (41) Google Scholar,22Armideo E. Callahan C. Madonia L. Immunotherapy for high-risk neuroblastoma: management of side effects and complications.J. Adv. Pract. Oncol. 2017; 8: 44-55https://doi.org/10.6004/jadpro.2017.8.1.4Crossref PubMed Google Scholar Immunotherapy has recently gained traction in high-risk NB treatment and improved survival rates in patients.22Armideo E. Callahan C. Madonia L. Immunotherapy for high-risk neuroblastoma: management of side effects and complications.J. Adv. Pract. Oncol. 2017; 8: 44-55https://doi.org/10.6004/jadpro.2017.8.1.4Crossref PubMed Google Scholar,23Yu A.L. Gilman A.L. Ozkaynak M.F. London W.B. Kreissman S.G. Chen H.X. Smith M. Anderson B. Villablanca J.G. Matthay K.K. et al.Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma.New Engl. J. Med. 2010; 363: 1324-1334https://doi.org/10.1056/nejmoa0911123Crossref PubMed Scopus (0) Google Scholar Immunotherapy treatment harnesses the CD8+T and natural killer (NK) cells to recognize, target, and eradicate malignant cells.24Ehlert K. Hansjuergens I. Zinke A. Otto S. Siebert N. Henze G. Lode H. Nivolumab and dinutuximab beta in two patients with refractory neuroblastoma.J. Immunother. Cancer. 2020; 8: e000540https://doi.org/10.1136/jitc-2020-000540Crossref PubMed Scopus (20) Google Scholar, 25Robert C. A decade of immune-checkpoint inhibitors in cancer therapy.Nat. Commun. 2020; 11: 3801https://doi.org/10.1038/s41467-020-17670-yCrossref PubMed Scopus (409) Google Scholar, 26Shirinbak S. Chan R.Y. Shahani S. Muthugounder S. Kennedy R. Hung L.T. Fernandez G.E. Hadjidaniel M.D. Moghimi B. Sheard M.A. et al.Combined immune checkpoint blockade increases CD8+CD28+PD-1+ effector T cells and provides a therapeutic strategy for patients with neuroblastoma.Oncoimmunology. 2021; 10: 1838140https://doi.org/10.1080/2162402x.2020.1838140Crossref PubMed Google Scholar The immunotherapy approach of using chimeric monoclonal anti-disialoganglioside (GD2) antibody dinutuximab has shown some success in NB clinical trials but is associated with severe side effects including neuropathic pain, infection, infusion-related reactions, capillary leak syndrome, decreased sensation, and paresthesia.23Yu A.L. Gilman A.L. Ozkaynak M.F. London W.B. Kreissman S.G. Chen H.X. Smith M. Anderson B. Villablanca J.G. Matthay K.K. et al.Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma.New Engl. J. Med. 2010; 363: 1324-1334https://doi.org/10.1056/nejmoa0911123Crossref PubMed Scopus (0) Google Scholar,27Morandi F. Frassoni F. Ponzoni M. Brignole C. 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Invest. 2018; 128: 4654-4668https://doi.org/10.1172/jci99317Crossref PubMed Scopus (0) Google Scholar Elevated levels of programmed death-ligand 1 (PD-L1 or CD274) have been found in NB tumors.28Mina M. Boldrini R. Citti A. Romania P. D'Alicandro V. De Ioris M. Castellano A. Furlanello C. Locatelli F. Fruci D. Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma.Oncoimmunology. 2015; 4: e1019981https://doi.org/10.1080/2162402x.2015.1019981Crossref PubMed Scopus (0) Google Scholar,30Zuo S. Sho M. Sawai T. Kanehiro H. Maeda K. Yoshida M. Tsukada R. Nomura M. Okuyama H. Potential role of the PD-L1 expression and tumor-infiltrating lymphocytes on neuroblastoma.Pediatr. Surg. Int. 2020; 36: 137-143https://doi.org/10.1007/s00383-019-04616-9Crossref PubMed Scopus (8) Google Scholar,31Saletta F. Vilain R.E. Gupta A.K. Nagabushan S. Yuksel A. Catchpoole D. Scolyer R.A. Byrne J.A. McCowage G. Programmed death-ligand 1 expression in a large cohort of pediatric patients with Solid tumor and association with clinicopathologic features in neuroblastoma.JCO Precision Oncol. 2017; 1: 1-12https://doi.org/10.1200/po.16.00049Crossref PubMed Google Scholar Two recent reports suggested that higher PD-L1 expression positively correlates with worse outcomes in NB patients.30Zuo S. Sho M. Sawai T. Kanehiro H. Maeda K. Yoshida M. Tsukada R. Nomura M. Okuyama H. Potential role of the PD-L1 expression and tumor-infiltrating lymphocytes on neuroblastoma.Pediatr. Surg. Int. 2020; 36: 137-143https://doi.org/10.1007/s00383-019-04616-9Crossref PubMed Scopus (8) Google Scholar,31Saletta F. Vilain R.E. Gupta A.K. Nagabushan S. Yuksel A. Catchpoole D. Scolyer R.A. Byrne J.A. McCowage G. 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Programmed death-ligand 1 expression in a large cohort of pediatric patients with Solid tumor and association with clinicopathologic features in neuroblastoma.JCO Precision Oncol. 2017; 1: 1-12https://doi.org/10.1200/po.16.00049Crossref PubMed Google Scholar, 32Nallasamy P. Chava S. Verma S.S. Mishra S. Gorantla S. Coulter D.W. Byrareddy S.N. Batra S.K. Gupta S.C. Challagundla K.B. PD-L1, inflammation, non-coding RNAs, and neuroblastoma: Immuno-oncology perspective.Semin. Cancer Biol. 2018; 52: 53-65https://doi.org/10.1016/j.semcancer.2017.11.009Crossref PubMed Scopus (49) Google Scholar, 33Wei J.S. Kuznetsov I.B. Zhang S. Song Y.K. Asgharzadeh S. Sindiri S. Wen X. Patidar R. Najaraj S. Walton A. et al.Clinically relevant cytotoxic immune cell signatures and clonal expansion of T-cell receptors in high-risk MYCN-not-amplified human neuroblastoma.Clin. 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MicroRNA therapeutics: towards a new era for the management of cancer and other diseases.Nat. Rev. Drug Discov. 2017; 16: 203-222https://doi.org/10.1038/nrd.2016.246Crossref PubMed Scopus (2698) Google Scholar Nervous system development during embryonic and pediatric stages requires precise epigenetic regulation of proliferation and differentiation pathways that are critically mediated by non-coding RNAs (ncRNAs). These ncRNAs, primarily miRs, also contribute to several tumor suppressive and oncogenic pathways within the tumor microenvironment. However, how miRs influence T and NK cell function in NB remains poorly understood. In this study, we found that" @default.
• W4220736375 created "2022-04-03" @default.
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• W4220736375 date "2022-06-01" @default.
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• W4220736375 title "miR-15a and miR-15b modulate natural killer and CD8+T-cell activation and anti-tumor immune response by targeting PD-L1 in neuroblastoma" @default.
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