{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T04:25:47Z","timestamp":1754195147863,"version":"3.37.3"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T00:00:00Z","timestamp":1634601600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T00:00:00Z","timestamp":1634601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004361","name":"Krebsliga Schweiz","doi-asserted-by":"publisher","award":["KFS-3958-08-2016-R"],"award-info":[{"award-number":["KFS-3958-08-2016-R"]}],"id":[{"id":"10.13039\/501100004361","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Children's Research Center (CRC) of the University Children's Hospital Zurich"},{"DOI":"10.13039\/501100006447","name":"Universit\u00e4t Z\u00fcrich","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006447","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Immunol Immunother"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Endemic Burkitt lymphoma (eBL) is an aggressive B cell cancer characterized by an <jats:italic>IgH\/c-myc<\/jats:italic> translocation and the harboring of Epstein\u2013Barr virus (EBV). Evidence accumulates that CD4\u2009+\u2009T cells might contribute to eBL pathogenesis. Here, we investigate the presence of CD4\u2009+\u2009T cells in primary eBL tissue and their potential dichotomous impact on an EBV-infected pre-eBL cell model using ex vivo material and in vitro co-cultures. In addition, we establish a novel method to study the effect of <jats:italic>IgH\/c-myc<\/jats:italic> translocation in primary B cells by employing a CRISPR\/Cas9 knock-in approach to introduce and tag de novo translocation. We unprecedently document that CD4\u2009+\u2009T cells are present in primary eBL tumor tissue. Furthermore, we demonstrate that CD4\u2009+\u2009T cells on the one hand suppress eBL development by killing pre-eBL cells lacking <jats:italic>IgH\/c-myc<\/jats:italic> translocation in vitro and on the other hand indirectly promote eBL development by inducing crucial EBV Latency III to Latency I switching in pre-eBL cells. Finally, we show that while the mere presence of an <jats:italic>IgH\/c-myc<\/jats:italic> translocation does not suffice to escape CD4\u2009+\u2009T-cell-mediated killing in vitro, the CD4\u2009+\u2009T-cell-mediated suppression of EBV\u2019s Latency III program in vivo may allow cells harboring an <jats:italic>IgH\/c-myc<\/jats:italic> translocation and additional mutations to evade immune control and proliferate by means of deregulated <jats:italic>c-myc<\/jats:italic> activity, resulting in neoplasia. Thus, our study highlights the dichotomous effects of CD4\u2009+\u2009T cells and the mechanisms involved in eBL pathogenesis, suggests mechanisms of their impact on eBL progression, and provides a novel in vitro model for further investigation of <jats:italic>IgH\/c-myc<\/jats:italic> translocation.<\/jats:p>","DOI":"10.1007\/s00262-021-03057-5","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T21:20:34Z","timestamp":1634678434000},"page":"1371-1392","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CD4\u00a0+\u00a0T cells are found within endemic Burkitt lymphoma and modulate Burkitt lymphoma precursor cell viability and expression of pathogenically relevant Epstein\u2013Barr virus genes"],"prefix":"10.1007","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5300-664X","authenticated-orcid":false,"given":"Semjon","family":"Sidorov","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lara","family":"Fux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katja","family":"Steiner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samyo","family":"Bounlom","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9193-5586","authenticated-orcid":false,"given":"Sabrina","family":"Traxel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3490-2419","authenticated-orcid":false,"given":"Tarik","family":"Azzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arbeneshe","family":"Berisha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2373-8804","authenticated-orcid":false,"given":"Christoph","family":"Berger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5746-8806","authenticated-orcid":false,"given":"Michele","family":"Bernasconi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7553-3712","authenticated-orcid":false,"given":"Felix K.","family":"Niggli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3569-6867","authenticated-orcid":false,"given":"Yvonne","family":"Perner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1368-0028","authenticated-orcid":false,"given":"Sugeshnee","family":"Pather","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6552-8629","authenticated-orcid":false,"given":"Werner","family":"Kempf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2712-1374","authenticated-orcid":false,"given":"David","family":"Nadal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3238-5120","authenticated-orcid":false,"given":"Simone","family":"B\u00fcrgler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,10,19]]},"reference":[{"issue":"3","key":"3057_CR1","doi-asserted-by":"publisher","first-page":"166","DOI":"10.5555\/afhs.2007.7.3.166","volume":"7","author":"J Orem","year":"2007","unstructured":"Orem J, Mbidde EK, Lambert B, de Sanjose S, Weiderpass E (2007) Burkitt\u2019s lymphoma in Africa, a review of the epidemiology and etiology. Afr Health Sci 7(3):166\u2013175. https:\/\/doi.org\/10.5555\/afhs.2007.7.3.166","journal-title":"Afr Health Sci"},{"issue":"11","key":"3057_CR2","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1182\/blood-2012-03-415380","volume":"120","author":"GD Victora","year":"2012","unstructured":"Victora GD, Dominguez-Sola D, Holmes AB, Deroubaix S, Dalla-Favera R, Nussenzweig MC (2012) Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood 120(11):2240\u20132248. https:\/\/doi.org\/10.1182\/blood-2012-03-415380","journal-title":"Blood"},{"key":"3057_CR3","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a014282","author":"R Schmitz","year":"2014","unstructured":"Schmitz R, Ceribelli M, Pittaluga S, Wright G, Staudt LM (2014) Oncogenic mechanisms in Burkitt lymphoma. Cold Spring Harb Perspect Med. https:\/\/doi.org\/10.1101\/cshperspect.a014282","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"13","key":"3057_CR4","doi-asserted-by":"publisher","first-page":"5857","DOI":"10.1073\/pnas.88.13.5857","volume":"88","author":"PE Neiman","year":"1991","unstructured":"Neiman PE, Thomas SJ, Loring G (1991) Induction of apoptosis during normal and neoplastic B-cell development in the bursa of Fabricius. Proc Natl Acad Sci USA 88(13):5857\u20135861. https:\/\/doi.org\/10.1073\/pnas.88.13.5857","journal-title":"Proc Natl Acad Sci USA"},{"issue":"12","key":"3057_CR5","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1038\/ng.2468","volume":"44","author":"C Love","year":"2012","unstructured":"Love C, Sun Z, Jima D, Li G, Zhang J, Miles R, Richards KL, Dunphy CH, Choi WW, Srivastava G, Lugar PL, Rizzieri DA, Lagoo AS, Bernal-Mizrachi L, Mann KP, Flowers CR, Naresh KN, Evens AM, Chadburn A, Gordon LI, Czader MB, Gill JI, Hsi ED, Greenough A, Moffitt AB, McKinney M, Banerjee A, Grubor V, Levy S, Dunson DB, Dave SS (2012) The genetic landscape of mutations in Burkitt lymphoma. Nat Genet 44(12):1321\u20131325. https:\/\/doi.org\/10.1038\/ng.2468","journal-title":"Nat Genet"},{"issue":"9","key":"3057_CR6","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.1002\/ijc.30885","volume":"141","author":"AR Mawson","year":"2017","unstructured":"Mawson AR, Majumdar S (2017) Malaria, Epstein-Barr virus infection and the pathogenesis of Burkitt\u2019s lymphoma. Int J Cancer 141(9):1849\u20131855. https:\/\/doi.org\/10.1002\/ijc.30885","journal-title":"Int J Cancer"},{"issue":"10","key":"3057_CR7","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1038\/nrc1452","volume":"4","author":"LS Young","year":"2004","unstructured":"Young LS, Rickinson AB (2004) Epstein-Barr virus: 40 years on. Nat Rev Cancer 4(10):757\u2013768. https:\/\/doi.org\/10.1038\/nrc1452","journal-title":"Nat Rev Cancer"},{"issue":"23","key":"3057_CR8","doi-asserted-by":"publisher","first-page":"9558","DOI":"10.1073\/pnas.86.23.9558","volume":"86","author":"JI Cohen","year":"1989","unstructured":"Cohen JI, Wang F, Mannick J, Kieff E (1989) Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. Proc Natl Acad Sci USA 86(23):9558\u20139562. https:\/\/doi.org\/10.1073\/pnas.86.23.9558","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"3057_CR9","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/0042-6822(92)90307-b","volume":"187","author":"BM Kerr","year":"1992","unstructured":"Kerr BM, Lear AL, Rowe M, Croom-Carter D, Young LS, Rookes SM, Gallimore PH, Rickinson AB (1992) Three transcriptionally distinct forms of Epstein-Barr virus latency in somatic cell hybrids: cell phenotype dependence of virus promoter usage. Virology 187(1):189\u2013201. https:\/\/doi.org\/10.1016\/0042-6822(92)90307-b","journal-title":"Virology"},{"issue":"3","key":"3057_CR10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004656","volume":"11","author":"AM Price","year":"2015","unstructured":"Price AM, Luftig MA (2015) To be or not IIb: a multi-step process for Epstein-Barr virus latency establishment and consequences for B cell tumorigenesis. PLoS Pathog 11(3):e1004656. https:\/\/doi.org\/10.1371\/journal.ppat.1004656","journal-title":"PLoS Pathog"},{"issue":"18","key":"3057_CR11","doi-asserted-by":"publisher","first-page":"8649","DOI":"10.1128\/jvi.75.18.8649-8659.2001","volume":"75","author":"A Leen","year":"2001","unstructured":"Leen A, Meij P, Redchenko I, Middeldorp J, Bloemena E, Rickinson A, Blake N (2001) Differential immunogenicity of Epstein-Barr virus latent-cycle proteins for human CD4(+) T-helper 1 responses. J Virol 75(18):8649\u20138659. https:\/\/doi.org\/10.1128\/jvi.75.18.8649-8659.2001","journal-title":"J Virol"},{"key":"3057_CR12","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1146\/annurev.immunol.25.022106.141553","volume":"25","author":"AD Hislop","year":"2007","unstructured":"Hislop AD, Taylor GS, Sauce D, Rickinson AB (2007) Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol 25:587\u2013617. https:\/\/doi.org\/10.1146\/annurev.immunol.25.022106.141553","journal-title":"Annu Rev Immunol"},{"issue":"3","key":"3057_CR13","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/s1074-7613(00)80622-6","volume":"9","author":"GJ Babcock","year":"1998","unstructured":"Babcock GJ, Decker LL, Volk M, Thorley-Lawson DA (1998) EBV persistence in memory B cells in vivo. Immunity 9(3):395\u2013404. https:\/\/doi.org\/10.1016\/s1074-7613(00)80622-6","journal-title":"Immunity"},{"issue":"9","key":"3057_CR14","doi-asserted-by":"publisher","first-page":"2500","DOI":"10.1002\/eji.200324794","volume":"34","author":"J Mautner","year":"2004","unstructured":"Mautner J, Pich D, Nimmerjahn F, Milosevic S, Adhikary D, Christoph H, Witter K, Bornkamm GW, Hammerschmidt W, Behrends U (2004) Epstein-Barr virus nuclear antigen 1 evades direct immune recognition by CD4+ T helper cells. Eur J Immunol 34(9):2500\u20132509. https:\/\/doi.org\/10.1002\/eji.200324794","journal-title":"Eur J Immunol"},{"issue":"4","key":"3057_CR15","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.cell.2004.08.006","volume":"118","author":"AR Ramiro","year":"2004","unstructured":"Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, Muramatsu M, Honjo T, Nussenzweig A, Nussenzweig MC (2004) AID is required for c-myc\/IgH chromosome translocations in vivo. Cell 118(4):431\u2013438. https:\/\/doi.org\/10.1016\/j.cell.2004.08.006","journal-title":"Cell"},{"issue":"6","key":"3057_CR16","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1084\/jem.20160120","volume":"213","author":"JS Kalchschmidt","year":"2016","unstructured":"Kalchschmidt JS, Bashford-Rogers R, Paschos K, Gillman AC, Styles CT, Kellam P, Allday MJ (2016) Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells. J Exp Med 213(6):921\u2013928. https:\/\/doi.org\/10.1084\/jem.20160120","journal-title":"J Exp Med"},{"issue":"5","key":"3057_CR17","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1016\/s1097-2765(02)00522-1","volume":"9","author":"H Tanaka","year":"2002","unstructured":"Tanaka H, Matsumura I, Ezoe S, Satoh Y, Sakamaki T, Albanese C, Machii T, Pestell RG, Kanakura Y (2002) E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell 9(5):1017\u20131029. https:\/\/doi.org\/10.1016\/s1097-2765(02)00522-1","journal-title":"Mol Cell"},{"issue":"11","key":"3057_CR18","doi-asserted-by":"publisher","first-page":"6055","DOI":"10.1073\/pnas.100119497","volume":"97","author":"ED Cahir-McFarland","year":"2000","unstructured":"Cahir-McFarland ED, Davidson DM, Schauer SL, Duong J, Kieff E (2000) NF-kappa B inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells. Proc Natl Acad Sci USA 97(11):6055\u20136060. https:\/\/doi.org\/10.1073\/pnas.100119497","journal-title":"Proc Natl Acad Sci USA"},{"issue":"39","key":"3057_CR19","doi-asserted-by":"publisher","first-page":"36671","DOI":"10.1074\/jbc.M203213200","volume":"277","author":"Z You","year":"2002","unstructured":"You Z, Madrid LV, Saims D, Sedivy J, Wang CY (2002) c-Myc sensitizes cells to tumor necrosis factor-mediated apoptosis by inhibiting nuclear factor kappa B transactivation. J Biol Chem 277(39):36671\u201336677. https:\/\/doi.org\/10.1074\/jbc.M203213200","journal-title":"J Biol Chem"},{"issue":"6","key":"3057_CR20","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1002\/ijc.1404","volume":"93","author":"A Pajic","year":"2001","unstructured":"Pajic A, Staege MS, Dudziak D, Schuhmacher M, Spitkovsky D, Eissner G, Brielmeier M, Polack A, Bornkamm GW (2001) Antagonistic effects of c-myc and Epstein-Barr virus latent genes on the phenotype of human B cells. Int J Cancer 93(6):810\u2013816. https:\/\/doi.org\/10.1002\/ijc.1404","journal-title":"Int J Cancer"},{"issue":"10","key":"3057_CR21","doi-asserted-by":"publisher","first-page":"5014","DOI":"10.1128\/jvi.02264-08","volume":"83","author":"N Faumont","year":"2009","unstructured":"Faumont N, Durand-Panteix S, Schlee M, Gr\u00f6mminger S, Schuhmacher M, H\u00f6lzel M, Laux G, Mailhammer R, Rosenwald A, Staudt LM, Bornkamm GW, Feuillard J (2009) c-Myc and Rel\/NF-kappaB are the two master transcriptional systems activated in the latency III program of Epstein-Barr virus-immortalized B cells. J Virol 83(10):5014\u20135027. https:\/\/doi.org\/10.1128\/jvi.02264-08","journal-title":"J Virol"},{"issue":"14","key":"3057_CR22","doi-asserted-by":"publisher","first-page":"6577","DOI":"10.1073\/pnas.92.14.6577","volume":"92","author":"JR M\u00fcller","year":"1995","unstructured":"M\u00fcller JR, Janz S, Goedert JJ, Potter M, Rabkin CS (1995) Persistence of immunoglobulin heavy chain\/c-myc recombination-positive lymphocyte clones in the blood of human immunodeficiency virus-infected homosexual men. Proc Natl Acad Sci USA 92(14):6577\u20136581. https:\/\/doi.org\/10.1073\/pnas.92.14.6577","journal-title":"Proc Natl Acad Sci USA"},{"issue":"25","key":"3057_CR23","doi-asserted-by":"publisher","first-page":"3011","DOI":"10.1038\/sj.onc.1201156","volume":"14","author":"V Roschke","year":"1997","unstructured":"Roschke V, Kopantzev E, Dertzbaugh M, Rudikoff S (1997) Chromosomal translocations deregulating c-myc are associated with normal immune responses. Oncogene 14(25):3011\u20133016. https:\/\/doi.org\/10.1038\/sj.onc.1201156","journal-title":"Oncogene"},{"issue":"Pt 12","key":"3057_CR24","doi-asserted-by":"publisher","first-page":"3051","DOI":"10.1099\/0022-1317-82-12-3051","volume":"82","author":"A Pajic","year":"2001","unstructured":"Pajic A, Polack A, Staege MS, Spitkovsky D, Baier B, Bornkamm GW, Laux G (2001) Elevated expression of c-myc in lymphoblastoid cells does not support an Epstein-Barr virus latency III-to-I switch. J Gen Virol 82(Pt 12):3051\u20133055. https:\/\/doi.org\/10.1099\/0022-1317-82-12-3051","journal-title":"J Gen Virol"},{"issue":"19","key":"3057_CR25","doi-asserted-by":"publisher","first-page":"10411","DOI":"10.1073\/pnas.93.19.10411","volume":"93","author":"A Polack","year":"1996","unstructured":"Polack A, H\u00f6rtnagel K, Pajic A, Christoph B, Baier B, Falk M, Mautner J, Geltinger C, Bornkamm GW, Kempkes B (1996) c-myc activation renders proliferation of Epstein-Barr virus (EBV)-transformed cells independent of EBV nuclear antigen 2 and latent membrane protein 1. Proc Natl Acad Sci USA 93(19):10411\u201310416. https:\/\/doi.org\/10.1073\/pnas.93.19.10411","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"3057_CR26","doi-asserted-by":"publisher","first-page":"92","DOI":"10.4049\/jimmunol.1100590","volume":"187","author":"HM Long","year":"2011","unstructured":"Long HM, Leese AM, Chagoury OL, Connerty SR, Quarcoopome J, Quinn LL, Shannon-Lowe C, Rickinson AB (2011) Cytotoxic CD4+ T cell responses to EBV contrast with CD8 responses in breadth of lytic cycle antigen choice and in lytic cycle recognition. J Immunol (Baltimore Md: 1950) 187(1):92\u2013101. https:\/\/doi.org\/10.4049\/jimmunol.1100590","journal-title":"J Immunol (Baltimore Md: 1950)"},{"issue":"10","key":"3057_CR27","doi-asserted-by":"publisher","first-page":"5895","DOI":"10.4049\/jimmunol.0902850","volume":"184","author":"A Merlo","year":"2010","unstructured":"Merlo A, Turrini R, Bobisse S, Zamarchi R, Alaggio R, Dolcetti R, Mautner J, Zanovello P, Amadori A, Rosato A (2010) Virus-specific cytotoxic CD4+ T cells for the treatment of EBV-related tumors. J Immunol (Baltimore, Md: 1950) 184(10):5895\u20135902. https:\/\/doi.org\/10.4049\/jimmunol.0902850","journal-title":"J Immunol (Baltimore, Md: 1950)"},{"issue":"8","key":"3057_CR28","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1093\/intimm\/10.8.1149","volume":"10","author":"AD Wilson","year":"1998","unstructured":"Wilson AD, Redchenko I, Williams NA, Morgan AJ (1998) CD4+ T cells inhibit growth of Epstein-Barr virus-transformed B cells through CD95-CD95 ligand-mediated apoptosis. Int Immunol 10(8):1149\u20131157. https:\/\/doi.org\/10.1093\/intimm\/10.8.1149","journal-title":"Int Immunol"},{"issue":"6","key":"3057_CR29","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1002\/ijc.2910130617","volume":"13","author":"EA Svedmyr","year":"1974","unstructured":"Svedmyr EA, Deinhardt F, Klein G (1974) Sensitivity of different target cells to the killing action of peripheral lymphocytes stimulated by autologous lymphoblastoid cell lines. Int J Cancer 13(6):891\u2013903. https:\/\/doi.org\/10.1002\/ijc.2910130617","journal-title":"Int J Cancer"},{"issue":"2","key":"3057_CR30","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1002\/path.4459","volume":"235","author":"M Vockerodt","year":"2015","unstructured":"Vockerodt M, Yap LF, Shannon-Lowe C, Curley H, Wei W, Vrzalikova K, Murray PG (2015) The Epstein-Barr virus and the pathogenesis of lymphoma. J Pathol 235(2):312\u2013322. https:\/\/doi.org\/10.1002\/path.4459","journal-title":"J Pathol"},{"issue":"25","key":"3057_CR31","doi-asserted-by":"publisher","first-page":"5600","DOI":"10.1182\/blood-2010-03-275917","volume":"116","author":"M Guech-Ongey","year":"2010","unstructured":"Guech-Ongey M, Simard EP, Anderson WF, Engels EA, Bhatia K, Devesa SS, Mbulaiteye SM (2010) AIDS-related Burkitt lymphoma in the United States: what do age and CD4 lymphocyte patterns tell us about etiology and\/or biology? Blood 116(25):5600\u20135604. https:\/\/doi.org\/10.1182\/blood-2010-03-275917","journal-title":"Blood"},{"issue":"5","key":"3057_CR32","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1073\/pnas.1120587109","volume":"109","author":"N Nagy","year":"2012","unstructured":"Nagy N, Adori M, Rasul A, Heuts F, Salamon D, Ujv\u00e1ri D, Madapura HS, Leveau B, Klein G, Klein E (2012) Soluble factors produced by activated CD4+ T cells modulate EBV latency. Proc Natl Acad Sci USA 109(5):1512\u20131517. https:\/\/doi.org\/10.1073\/pnas.1120587109","journal-title":"Proc Natl Acad Sci USA"},{"issue":"5","key":"3057_CR33","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1002\/ijc.10417","volume":"99","author":"K Pokrovskaja","year":"2002","unstructured":"Pokrovskaja K, Ehlin-Henriksson B, Kiss C, Challa A, Gordon J, Gogolak P, Klein G, Szekely L (2002) CD40 ligation downregulates EBNA-2 and LMP-1 expression in EBV-transformed lymphoblastoid cell lines. Int J Cancer 99(5):705\u2013712. https:\/\/doi.org\/10.1002\/ijc.10417","journal-title":"Int J Cancer"},{"issue":"4","key":"3057_CR34","doi-asserted-by":"publisher","first-page":"6461","DOI":"10.18632\/oncotarget.14120","volume":"8","author":"V Mordasini","year":"2017","unstructured":"Mordasini V, Ueda S, Aslandogmus R, Berger C, Gysin C, H\u00fchn D, Sartori AA, Bernasconi M, Nadal D (2017) Activation of ATR-Chk1 pathway facilitates EBV-mediated transformation of primary tonsillar B-cells. Oncotarget 8(4):6461\u20136474. https:\/\/doi.org\/10.18632\/oncotarget.14120","journal-title":"Oncotarget"},{"issue":"46","key":"3057_CR35","doi-asserted-by":"publisher","first-page":"16286","DOI":"10.1073\/pnas.0407320101","volume":"101","author":"E Johannsen","year":"2004","unstructured":"Johannsen E, Luftig M, Chase MR, Weicksel S, Cahir-McFarland E, Illanes D, Sarracino D, Kieff E (2004) Proteins of purified Epstein-Barr virus. Proc Natl Acad Sci USA 101(46):16286\u201316291. https:\/\/doi.org\/10.1073\/pnas.0407320101","journal-title":"Proc Natl Acad Sci USA"},{"issue":"9","key":"3057_CR36","doi-asserted-by":"publisher","first-page":"7075","DOI":"10.1128\/jvi.72.9.7075-7083.1998","volume":"72","author":"Q Tao","year":"1998","unstructured":"Tao Q, Robertson KD, Manns A, Hildesheim A, Ambinder RF (1998) The Epstein-Barr virus major latent promoter Qp is constitutively active, hypomethylated, and methylation sensitive. J Virol 72(9):7075\u20137083. https:\/\/doi.org\/10.1128\/jvi.72.9.7075-7083.1998","journal-title":"J Virol"},{"issue":"5","key":"3057_CR37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007748","volume":"15","author":"B Chatterjee","year":"2019","unstructured":"Chatterjee B, Deng Y, Holler A, Nunez N, Azzi T, Vanoaica LD, M\u00fcller A, Zdimerova H, Antsiferova O, Zbinden A, Capaul R, Dreyer JH, Nadal D, Becher B, Robinson MD, Stauss H, M\u00fcnz C (2019) CD8+ T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo. PLoS Pathog 15(5):e1007748. https:\/\/doi.org\/10.1371\/journal.ppat.1007748","journal-title":"PLoS Pathog"},{"issue":"2","key":"3057_CR38","doi-asserted-by":"publisher","first-page":"79","DOI":"10.7497\/j.issn.2095-3941.2015.0029","volume":"12","author":"N Karachaliou","year":"2015","unstructured":"Karachaliou N, Cao MG, Teixid\u00f3 C, Viteri S, Morales-Espinosa D, Santarpia M, Rosell R (2015) Understanding the function and dysfunction of the immune system in lung cancer: the role of immune checkpoints. Cancer Biol Med 12(2):79\u201386. https:\/\/doi.org\/10.7497\/j.issn.2095-3941.2015.0029","journal-title":"Cancer Biol Med"},{"issue":"4","key":"3057_CR39","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1002\/1097-0320(20011201)45:4<237::aid-cyto10024>3.0.co;2-j","volume":"45","author":"AM Steff","year":"2001","unstructured":"Steff AM, Fortin M, Arguin C, Hugo P (2001) Detection of a decrease in green fluorescent protein fluorescence for the monitoring of cell death: an assay amenable to high-throughput screening technologies. Cytometry 45(4):237\u2013243. https:\/\/doi.org\/10.1002\/1097-0320(20011201)45:4%3c237::aid-cyto10024%3e3.0.co;2-j","journal-title":"Cytometry"},{"issue":"13","key":"3057_CR40","doi-asserted-by":"publisher","first-page":"4625","DOI":"10.1073\/pnas.0306482101","volume":"101","author":"CJ Farrell","year":"2004","unstructured":"Farrell CJ, Lee JM, Shin EC, Cebrat M, Cole PA, Hayward SD (2004) Inhibition of Epstein-Barr virus-induced growth proliferation by a nuclear antigen EBNA2-TAT peptide. Proc Natl Acad Sci USA 101(13):4625\u20134630. https:\/\/doi.org\/10.1073\/pnas.0306482101","journal-title":"Proc Natl Acad Sci USA"},{"issue":"10","key":"3057_CR41","doi-asserted-by":"publisher","first-page":"2065","DOI":"10.1084\/jem.20160248","volume":"213","author":"T Tagawa","year":"2016","unstructured":"Tagawa T, Albanese M, Bouvet M, Moosmann A, Mautner J, Heissmeyer V, Zielinski C, Lutter D, Hoser J, Hastreiter M, Hayes M, Sugden B, Hammerschmidt W (2016) Epstein-Barr viral miRNAs inhibit antiviral CD4+ T cell responses targeting IL-12 and peptide processing. J Exp Med 213(10):2065\u20132080. https:\/\/doi.org\/10.1084\/jem.20160248","journal-title":"J Exp Med"},{"key":"3057_CR42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402382","author":"JM God","year":"2015","unstructured":"God JM, Cameron C, Figueroa J, Amria S, Hossain A, Kempkes B, Bornkamm GW, Stuart RK, Blum JS, Haque A (2015) Elevation of c-MYC disrupts HLA Class II\u2013mediated immune recognition of human B Cell tumors. J Immunol. https:\/\/doi.org\/10.4049\/jimmunol.1402382","journal-title":"J Immunol"},{"issue":"5","key":"3057_CR43","doi-asserted-by":"publisher","first-page":"4481","DOI":"10.1128\/JVI.73.5.4481-4484.1999","volume":"73","author":"C Kaiser","year":"1999","unstructured":"Kaiser C, Laux G, Eick D, Jochner N, Bornkamm GW, Kempkes B (1999) The proto-oncogene c-myc is a direct target gene of Epstein-Barr virus nuclear antigen 2. J Virol 73(5):4481\u20134484. https:\/\/doi.org\/10.1128\/JVI.73.5.4481-4484.1999","journal-title":"J Virol"},{"issue":"2","key":"3057_CR44","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1002\/j.1460-2075.1996.tb00367.x","volume":"15","author":"N Jochner","year":"1996","unstructured":"Jochner N, Eick D, Zimber-Strobl U, Pawlita M, Bornkamm GW, Kempkes B (1996) Epstein-Barr virus nuclear antigen 2 is a transcriptional suppressor of the immunoglobulin mu gene: implications for the expression of the translocated c-myc gene in Burkitt\u2019s lymphoma cells. EMBO J 15(2):375\u2013382. https:\/\/doi.org\/10.1002\/j.1460-2075.1996.tb00367.x","journal-title":"EMBO J"},{"key":"3057_CR45","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/B978-0-12-386469-7.00004-9","volume-title":"Advances in cancer research","author":"LR Thomas","year":"2011","unstructured":"Thomas LR, Tansey WP (2011) Proteolytic control of the oncoprotein transcription factor Myc. In: Klein G (ed) Advances in cancer research, vol 110. Academic Press, pp 77\u2013106. https:\/\/doi.org\/10.1016\/B978-0-12-386469-7.00004-9"}],"container-title":["Cancer Immunology, Immunotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-021-03057-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00262-021-03057-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-021-03057-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T02:03:52Z","timestamp":1653098632000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00262-021-03057-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,19]]},"references-count":45,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["3057"],"URL":"https:\/\/doi.org\/10.1007\/s00262-021-03057-5","relation":{},"ISSN":["0340-7004","1432-0851"],"issn-type":[{"type":"print","value":"0340-7004"},{"type":"electronic","value":"1432-0851"}],"subject":[],"published":{"date-parts":[[2021,10,19]]},"assertion":[{"value":"9 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 October 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was performed in accordance with the 1964 Declaration of Helsinki. The use of paraffin tissue recuts from eBL patients and palatine tonsils from children undergoing routine tonsillectomy was approved by the regional ethics committee (University of the Witwatersrand, Johannesburg, South Africa, Nr. M180294 and Kantonale Ethikkommission Z\u00fcrich, KEK-ZH Nr. StV 40\/05, respectively).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The patients and the parents or guardians of tonsillectomy subjects gave informed consent for use of samples.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}]}}