TH-MYCN tumors, but not tumor-derived cell lines, are adrenergic lineage, GD2+, and responsive to anti-GD2 antibody therapy

References

• Hwang WL, Wolfson RL, Niemierko A, Marcus KJ, DuBois SG, Haas-Kogan D. Clinical impact of tumor mutational burden in neuroblastoma. J Natl Cancer Inst. 2019;111:695–13. doi:10.1093/jnci/djy157.
   PubMedGoogle Scholar
• Noskova H, Kyr M, Pal K, Merta T, Mudry P, Polaskova K, Ivkovic TC, Adamcova S, Hornakova T, Jezova M, et al. Assessment of tumor mutational burden in pediatric tumors by real-life whole-exome sequencing and in silico simulation of targeted gene panels: how the choice of method could affect the clinical decision? Cancers. 2020;12:230. doi:10.3390/cancers12010230.
   PubMed Web of Science ®Google Scholar
• Coughlan D, Gianferante M, Lynch CF, Stevens JL, Harlan LC. Treatment and survival of childhood neuroblastoma: evidence from a population-based study in the United States. Pediatr Hematol Oncol. 2017;34:320–330. doi:10.1080/08880018.2017.1373315.
   PubMed Web of Science ®Google Scholar
• Castriconi R, Dondero A, Bellora F, Moretta L, Castellano A, Locatelli F, Corrias MV, Moretta A, Bottino C. Neuroblastoma-Derived TGF-β1 modulates the chemokine receptor repertoire of human resting NK cells. J Immunol. 2013;190:5321–5328. doi:10.4049/jimmunol.1202693.
   PubMed Web of Science ®Google Scholar
• Brandetti E, Veneziani I, Melaiu O, Pezzolo A, Castellano A, Boldrini R, Ferretti E, Fruci D, Moretta L, Pistoia V, et al. MYCN is an immunosuppressive oncogene dampening the expression of ligands for NK-cell-activating receptors in human high-risk neuroblastoma. OncoImmunology. 2017;6:e1316439. doi:10.1080/2162402X.2017.1316439.
   PubMed Web of Science ®Google Scholar
• Hashimoto O, Yoshida M, Koma Y, Yanai T, Hasegawa D, Kosaka Y, Nishimura N, Yokozaki H. Collaboration of cancer-associated fibroblasts and tumour-associated macrophages for neuroblastoma development: the role of non-tumour stromal cells in neuroblastoma progression. J Pathol. 2016;240:211–223. doi:10.1002/path.4769.
   PubMed Web of Science ®Google Scholar
• Mody R, Naranjo A, Van Ryn C, Yu AL, London WB, Shulkin BL, Parisi MT, Servaes SEN, Diccianni MB, Sondel PM, et al. Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Lancet Oncol. 2017;18:946–957. doi:10.1016/S1470-2045(17)30355-8.
   PubMed Web of Science ®Google Scholar
• Mody R, Yu AL, Naranjo A, Zhang FF, London WB, Shulkin BL, Parisi MT, Servaes SEN, Diccianni MB, Hank JA, et al. Irinotecan, temozolomide, and dinutuximab with GM-CSF in children with refractory or relapsed neuroblastoma: a report from the children’s oncology group. J Clin Oncol Off J Am Soc Clin Oncol. 2020;38:2160–2169. doi:10.1200/JCO.20.00203.
   PubMed Web of Science ®Google Scholar
• Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363:7554–7564. doi:10.1056/NEJMoa0911123.
   Web of Science ®Google Scholar
• Yu AL, Gilman AL, Ozkaynak MF, Naranjo A, Diccianni MB, Gan J, Hank JA, Batova A, London WB, Tenney SC, et al. Long-term follow-up of a phase iii study of ch14.18 (dinutuximab) + cytokine immunotherapy in children with high-risk neuroblastoma: COG Study ANBL0032. Clin Cancer Res Off J Am Assoc Cancer Res. 2021;27:2179–2189. doi:10.1158/1078-0432.CCR-20-3909.
   PubMed Web of Science ®Google Scholar
• Hanahan D. Transgenic mice as probes into complex systems. Science. 1989;246:1265–1275. doi:10.1126/science.2686032.
   PubMed Web of Science ®Google Scholar
• Roussel MF, Stripay JL. Modeling pediatric medulloblastoma. Brain Pathol. 2019:12803. doi:10.1111/bpa.12803.
   Web of Science ®Google Scholar
• Feuring-Buske M, Gerhard B, Cashman J, Humphries RK, Eaves CJ, Hogge DE. Improved engraftment of human acute myeloid leukemia progenitor cells in beta 2-microglobulin-deficient NOD/SCID mice and in NOD/SCID mice transgenic for human growth factors. Leukemia. 2003;17:760–763. doi:10.1038/sj.leu.2402882.
   PubMed Web of Science ®Google Scholar
• Weiss WA. Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 1997;16:2985–2995. doi:10.1093/emboj/16.11.2985.
   PubMed Web of Science ®Google Scholar
• Rasmuson A, Segerström L, Nethander M, Finnman J, Elfman LHM, Javanmardi N, Nilsson S, Johnsen JI, Martinsson T, Kogner P, et al. Tumor development, growth characteristics and spectrum of genetic aberrations in the TH-MYCN mouse model of neuroblastoma. PLoS ONE. 2012;7:e51297. doi:10.1371/journal.pone.0051297.
   PubMed Web of Science ®Google Scholar
• Hackett CS, Hodgson JG, Law ME, Fridlyand J, Osoegawa K, de Jong PJ, Nowak NJ, Pinkel D, Albertson DG, Jain A, et al. Genome-wide array CGH analysis of murine neuroblastoma reveals distinct genomic aberrations which parallel those in human tumors. Cancer Res. 2003;63(17):5266–5273.
   PubMed Web of Science ®Google Scholar
• Teitz T, Stanke JJ, Federico S, Bradley CL, Brennan R, Zhang J, Johnson MD, Sedlacik J, Inoue M, Zhang ZM, et al. Preclinical models for neuroblastoma: establishing a baseline for treatment. PloS One. 2011;6:e19133. doi:10.1371/journal.pone.0019133.
   PubMed Web of Science ®Google Scholar
• Moore HC, Wood KM, Jackson MS, Lastowska MA, Hall D, Imrie H, Redfern CPF, Lovat PE, Ponthan F, O’Toole K, et al. Histological profile of tumours from MYCN transgenic mice. J Clin Pathol. 2008;61:1098–1103. doi:10.1136/jcp.2007.054627.
   PubMed Web of Science ®Google Scholar
• Webb ER, Lanati S, Wareham C, Easton A, Dunn SN, Inzhelevskaya T, Sadler FM, James S, Ashton-Key M, Cragg MS, et al. Immune characterization of pre-clinical murine models of neuroblastoma. Sci Rep. 2020;10:16695. doi:10.1038/s41598-020-73695-9.
   PubMed Web of Science ®Google Scholar
• Kroesen M, Brok IC, Reijnen D, van Hout-kuijer MA, Zeelenberg IS, Den Brok MH, Hoogerbrugge PM, Adema GJ. Intra-adrenal murine TH-MYCN neuroblastoma tumors grow more aggressive and exhibit a distinct tumor microenvironment relative to their subcutaneous equivalents. Cancer Immunol Immunother CII. 2015;64:563–572. doi:10.1007/s00262-015-1663-y.
   PubMed Web of Science ®Google Scholar
• Voeller J, Erbe AK, Slowinski J, Rasmussen K, Carlson PM, Hoefges A, VandenHeuvel S, Stuckwisch A, Wang X, Gillies SD, et al. Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition. J Immunother Cancer. 2019;7:344. doi:10.1186/s40425-019-0823-6.
   PubMed Web of Science ®Google Scholar
• Boeva V, Louis-Brennetot C, Peltier A, Durand S, Pierre-Eugene C, Raynal V, Etchevers HC, Thomas S, Lermine A, Daudigeos-Dubus E, et al. Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries. Nat Genet. 2017;49:2179–2189. doi:10.1038/ng.3921.
   Web of Science ®Google Scholar
• van Groningen T, Koster J, Valentijn LJ, van Groningen T, Zwijnenburg DA, Akogul N, Hasselt NE, Broekmans M, Haneveld F, Nowakowska NE, et al. Neuroblastoma is composed of two super-enhancer-associated differentiation states. Nat Genet. 2017;49(8):1261–1266. doi:10.1038/ng.3899.
   PubMed Web of Science ®Google Scholar
• Haraguchi S, Nakagawara A. A simple PCR method for rapid genotype analysis of the TH-MYCN transgenic mouse. PloS One. 2009;4:e6902. doi:10.1371/journal.pone.0006902.
   PubMed Web of Science ®Google Scholar
• Winter C, Pawel B, Seiser E, Zhao H, Raabe E, Wang Q, Judkins AR, Attiyeh E, Maris JM. Neural cell adhesion molecule (NCAM) isoform expression is associated with neuroblastoma differentiation status. Pediatr Blood Cancer. 2008;51:10–16. doi:10.1002/pbc.21475.
   PubMed Web of Science ®Google Scholar
• Phimister E, Kiely F, Kemshead JT, Patel K. Expression of neural cell adhesion molecule (NCAM) isoforms in neuroblastoma. J Clin Pathol. 1991;44:580–585. doi:10.1136/jcp.44.7.580.
   PubMed Web of Science ®Google Scholar
• Bryson GJ, Lear D, Williamson R, Wong RCW. Detection of the CD56+/CD45- immunophenotype by flow cytometry in neuroendocrine malignancies. J Clin Pathol. 2002;55:535–537. doi:10.1136/jcp.55.7.535.
   PubMed Web of Science ®Google Scholar
• Bozzi F, Collini P, Aiello A, Barzanò E, Gambirasio F, Podda M, Meazza C, Ferrari A, Luksch R. Flow cytometric phenotype of rhabdomyosarcoma bone marrow metastatic cells and its implication in differential diagnosis with neuroblastoma. Anticancer Res. 2008;28:1565–1569.
   PubMed Web of Science ®Google Scholar
• Theodorakos I, Paterakis G, Papadakis V, Vicha A, Topakas G, Jencova P, Karchilaki E, Taparkou A, Tsagarakis N, Polychronopoulou S. Interference of bone marrow CD56+ mesenchymal stromal cells in minimal residual disease investigation of neuroblastoma and other CD45- /CD56+ pediatric malignancies using flow cytometry. Pediatr Blood Cancer. 2019;66:e27799. doi:10.1002/pbc.27799.
   PubMed Web of Science ®Google Scholar
• Hansford LM, Thomas WD, Keating JM, Burkhart CA, Peaston AE, Norris MD, Haber M, Armati PJ, Weiss WA, Marshall GM, et al. Mechanisms of embryonal tumor initiation: distinct roles for MycN expression and MYCN amplification. Proc Natl Acad Sci. 2004;101:12664–12669. doi:10.1073/pnas.0401083101.
   PubMed Web of Science ®Google Scholar
• Carlson L-M, Rasmuson A, Idborg H, Segerström L, Jakobsson P-J, Sveinbjörnsson B, Kogner P. Low-dose aspirin delays an inflammatory tumor progression in vivo in a transgenic mouse model of neuroblastoma. Carcinogenesis. 2013;34:1081–1088. doi:10.1093/carcin/bgt009.
   PubMed Web of Science ®Google Scholar
• Layer JP, Kronmüller MT, Quast T, van den Boorn-Konijnenberg D, Effern M, Hinze D, Althoff K, Schramm A, Westermann F, Peifer M, et al. Amplification of N-Myc is associated with a T-cell-poor microenvironment in metastatic neuroblastoma restraining interferon pathway activity and chemokine expression. Oncoimmunology. 2017;6:e1320626. doi:10.1080/2162402X.2017.1320626.
   PubMed Web of Science ®Google Scholar
• Asgharzadeh S, Salo JA, Ji L, Oberthuer A, Fischer M, Berthold F, Hadjidaniel M, Liu CWY, Metelitsa LS, Pique-Regi R, et al. Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:3525–3532. doi:10.1200/JCO.2011.40.9169.
   PubMed Web of Science ®Google Scholar
• Tarek N, Le Luduec J-B, Gallagher MM, Zheng J, Venstrom JM, Chamberlain E, Modak S, Heller G, Dupont B, Cheung NK, et al. Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J Clin Invest. 2012;122(9):3260–3270. doi:10.1186/s40425-019-0823-6.
   PubMed Web of Science ®Google Scholar
• Zobel MJ, Zamora AK, Wu H, Sun J, Lascano D, Malvar J, Wang L, Sheard MA, Seeger RC, Kim ES, et al. Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice. J Immunother Cancer. 2020;8:e001560. doi:10.1136/jitc-2020-001560.
   PubMed Web of Science ®Google Scholar
• Funaro A, Spagnoli GC, Ausiello CM, Alessio M, Roggero S, Delia D, Zaccolo M, Malavasi F. Involvement of the multilineage CD38 molecule in a unique pathway of cell activation and proliferation. J Immunol Baltim Md 1950. 1990;145:2390–2396.
   Google Scholar
• Chen Y-G, Chen J, Osborne MA, Chapman HD, Besra GS, Porcelli SA, Leiter EH, Wilson SB, Serreze DV. CD38 Is required for the peripheral survival of immunotolerogenic CD4 + invariant NK T cells in nonobese diabetic mice. J Immunol. 2006;177:10–16. doi:10.4049/jimmunol.177.5.2939.
   Web of Science ®Google Scholar
• Sconocchia G, Titus JA, Mazzoni A, Visintin A, Pericle F, Hicks SW, Malavasi F, Segal DM. CD38 triggers cytotoxic responses in activated human natural killer cells. Blood. 1999;94:3864–3871. doi:10.1182/blood.V94.11.3864.
   PubMed Web of Science ®Google Scholar
• Cornel AM, Mimpen IL, Nierkens S. MHC class I downregulation in cancer: underlying mechanisms and potential targets for cancer immunotherapy. Cancers. 2020;12:1760. doi:10.3390/cancers12071760.
   PubMed Web of Science ®Google Scholar
• Zingoni A, Molfetta R, Fionda C, Soriani A, Paolini R, Cippitelli M, Cerboni C, Santoni A. NKG2D and Its Ligands: ‘One for All, All for One’. Front Immunol. 2018;9:476. doi:10.3389/fimmu.2018.00476.
   PubMed Web of Science ®Google Scholar
• Huang Y, Tsubota S, Nishio N, Takahashi Y, Kadomatsu K. Combination of tumor necrosis factor-α and epidermal growth factor induces the adrenergic-to-mesenchymal transdifferentiation in SH-SY5Y neuroblastoma cells. Cancer Sci. 2021;112(2):715–724. doi:10.1111/cas.14760.
   PubMed Web of Science ®Google Scholar
• Shi H, Tao T, Abraham BJ, Durbin AD, Zimmerman MW, Kadoch C, Look AT. ARID1A loss in neuroblastoma promotes the adrenergic-to-mesenchymal transition by regulating enhancer-mediated gene expression. Sci Adv. 2020;6:eaaz3440. doi:10.1126/sciadv.aaz3440.
   PubMed Web of Science ®Google Scholar
• van Groningen T, Akogul N, Westerhout EM, van Groningen T, Chan A, Hasselt NE, Zwijnenburg DA, Broekmans M, Stroeken P, Haneveld F, et al. A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma. Nat Commun. 2019;10:1530. doi:10.1038/s41467-019-09470-w.
   PubMed Web of Science ®Google Scholar
• Heiss P, Bermatz S, Wehnes H, Heinzmann U, Senekowitsch-Schmidtke R. Distribution of disialoganglioside GD2-antigen and binding of anti-GD2 antibodies on spheroids of neuroblastoma cell line. Anticancer Res. 1997;17:3145–3147.
   PubMed Web of Science ®Google Scholar
• Kildisiute G, Kholosy WM, Young MD, Roberts K, Elmentaite R, van Hooff SR, Pacyna CN, Khabirova E, Piapi A, Thevanesan C, et al. Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell. Sci Adv. 2021;7. doi:10.1126/sciadv.abd3311.
   PubMed Web of Science ®Google Scholar
• Wolpaw AJ, Grossmann LD, Dong MM, Dessau JL, Dong MM, Aaron BJ, Brafford PA, Volgina D, Pascual-Pasto G, Rodriguez-Garcia A, et al. Epigenetic state determines inflammatory sensing in neuroblastoma. Proc Natl Acad Sci USA.2021;19(6). doi: 10.1073/pnas.2102358119.
   Google Scholar
• Wolf BJ, Choi JE, Exley MA. Novel approaches to exploiting invariant NKT cells in cancer immunotherapy. Front Immunol. 2018;9:384. doi:10.3389/fimmu.2018.00384.
   PubMed Web of Science ®Google Scholar
• Song L, Asgharzadeh S, Salo J, Engell K, Wu H-W, Sposto R, Ara T, Silverman AM, DeClerck YA, Seeger RC, et al. Valpha24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages. J Clin Invest. 2009;119:1524–1536. doi:10.1172/JCI37869.
   PubMed Web of Science ®Google Scholar
• Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–444. doi:10.1038/nature07205.
   PubMed Web of Science ®Google Scholar
• Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, Rimoldi M, Biswas SK, Allavena P, Mantovani A, et al. Macrophage polarization in tumour progression. Semin Cancer Biol. 2008;18:349–355. doi:10.1016/j.semcancer.2008.03.004.
   PubMed Web of Science ®Google Scholar
• Dysthe M, Parihar R. Myeloid-Derived suppressor cells in the tumor microenvironment. In Birbrair A, editor. Tumor Microenvironment. Cham, Switzerland: Springer International Publishing; 2020. p. 117–140. doi:10.1007/978-3-030-35723-8_8.
   Google Scholar
• Trotta R, Dal Col J, Yu J, Ciarlariello D, Thomas B, Zhang X, Allard J, Wei M, Mao H, Byrd JC, et al. TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. J Immunol. 2008;181:3784–3792. doi:10.4049/jimmunol.181.6.3784.
   PubMed Web of Science ®Google Scholar
• Tran HC, Wan Z, Sheard MA, Sun J, Jackson JR, Malvar J, Xu Y, Wang L, Sposto R, Kim ES, et al. TGFβR1 blockade with galunisertib (LY2157299) enhances anti-neuroblastoma activity of the anti-gd2 antibody dinutuximab (ch14.18) with natural killer cells. Clin Cancer Res Off J Am Assoc Cancer Res. 2017;23:804–813. doi:10.1158/1078-0432.CCR-16-1743.
   PubMed Web of Science ®Google Scholar
• Nguyen R, Moustaki A, Norrie JL, Brown S, Akers WJ, Shirinifard A, Dyer MA. Interleukin-15 enhances anti-GD2 antibody-mediated cytotoxicity in an orthotopic PDX model of neuroblastoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2019;25:7554–7564. doi:10.1158/1078-0432.CCR-19-1045.
   PubMed Web of Science ®Google Scholar
• Barry WE, Jackson JR, Asuelime GE, Wu H-W, Sun J, Wan Z, Malvar J, Sheard MA, Wang L, Seeger RC, et al. Activated natural killer cells in combination with Anti-GD2 antibody dinutuximab improve survival of mice after surgical resection of primary neuroblastoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2019;25:325–333. doi:10.1158/1078-0432.CCR-18-1317.
   PubMed Web of Science ®Google Scholar