{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T03:24:58Z","timestamp":1794367498786,"version":"4.9.0"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002081","name":"Irish Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002081","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["MCSA CoMAnD 101065377"],"award-info":[{"award-number":["MCSA CoMAnD 101065377"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"name":"AIRC MFAG Rif. 32713"},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA233490, U54CA272691"],"award-info":[{"award-number":["R01CA233490, U54CA272691"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Duke University Institutional Award"},{"DOI":"10.13039\/501100015570","name":"Blood Cancer UK","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100015570","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV\u207aDLBCL) is an aggressive lymphoma with poor outcomes and an incompletely understood pathogenesis, frequently attributed to immunosenescence. However, its occurrence across all age groups suggests alternative mechanisms. Here, we integrate functional profiling of peripheral antiviral T-cell immunity with high-dimensional spatial proteomics and mechanistic in vitro modelling to define the immunological landscape of EBV\u207aDLBCL. We show that both EBV\u207a and EBV\u207bDLBCL patients exhibit broad impairments in antiviral T-cell responses compared with healthy controls, affecting latent and lytic EBV antigens as well as non-EBV viral targets, with deficits most pronounced in EBV\u207a patients. Spatial proteomic analysis revealed that EBV\u207aDLBCL harbours a profoundly immunosuppressive tumour microenvironment characterised by relative loss of intratumoural CD8\u207a T cells, expansion of PD-1\u207a regulatory and exhausted T-cell populations and dense aggregates of PD-L1\u207a\/IDO1\u207a macrophages. Compared with EBV\u207a classical Hodgkin lymphoma and infectious mononucleosis, EBV\u207aDLBCL displayed the most marked macrophage-associated immunosuppressive signature and the lowest T-cell density. Suppressive myeloid niches were preferentially enriched around LMP1-expressing tumour cells, a feature not observed in the other EBV-associated conditions. Together, these findings indicate that EBV\u207aDLBCL is driven by the convergence of systemic antiviral immune dysfunction and an LMP1-dependent suppressive tumour microenvironment.<\/jats:p>","DOI":"10.1038\/s41375-026-02994-3","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T12:57:27Z","timestamp":1781096247000},"page":"1676-1687","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Loss of systemic anti-viral immunity and LMP1-driven suppressive myeloid tumour niches converge to shape the immunobiology of Epstein-Barr virus-positive diffuse large B-cell lymphoma"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1280-3439","authenticated-orcid":false,"given":"\u00c9anna","family":"Fennell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0782-6951","authenticated-orcid":false,"given":"Soi C.","family":"Law","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1909-7047","authenticated-orcid":false,"given":"Alexander C.","family":"Dowell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6324-661X","authenticated-orcid":false,"given":"Matthew R.","family":"Pugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8490-1356","authenticated-orcid":false,"given":"Christina M.","family":"Enright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aisling M.","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5266-380X","authenticated-orcid":false,"given":"Aoife S.","family":"Hennessy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciara I.","family":"Leahy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadezhda","family":"Nikulina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex G.","family":"Richter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Mundo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Leoncini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Lazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Chiara","family":"Siciliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan D.","family":"Dojcinov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Quintanilla-Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5755-8932","authenticated-orcid":false,"given":"Ken H.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1000-5393","authenticated-orcid":false,"given":"Maher K.","family":"Gandhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4807-2797","authenticated-orcid":false,"given":"Graham S.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0956-6468","authenticated-orcid":false,"given":"Paul G.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"2994_CR1","doi-asserted-by":"publisher","first-page":"5124","DOI":"10.1158\/1078-0432.CCR-06-2823","volume":"13","author":"T Oyama","year":"2007","unstructured":"Oyama T, Yamamoto K, Asano N, Oshiro A, Suzuki R, Kagami Y, et al. Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin Cancer Res. 2007;13:5124\u201332.","journal-title":"Clin Cancer Res"},{"key":"2994_CR2","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s12979-018-0130-y","volume":"15","author":"S Mancuso","year":"2018","unstructured":"Mancuso S, Carlisi M, Santoro M, Napolitano M, Raso S, Siragusa S. Immunosenescence and lymphomagenesis. Immun Ageing. 2018;15:22.","journal-title":"Immun Ageing"},{"key":"2994_CR3","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1182\/blood-2013-03-489708","volume":"122","author":"CY Ok","year":"2013","unstructured":"Ok CY, Papathomas TG, Medeiros LJ, Young KH. EBV-positive diffuse large B-cell lymphoma of the elderly. Blood. 2013;122:328\u201340.","journal-title":"Blood"},{"key":"2994_CR4","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1111\/j.1399-0039.2007.00891.x","volume":"70","author":"FT Hakim","year":"2007","unstructured":"Hakim FT, Gress RE. Immunosenescence: deficits in adaptive immunity in the elderly. Tissue Antigens. 2007;70:179\u201389.","journal-title":"Tissue Antigens"},{"key":"2994_CR5","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1093\/annonc\/mdu556","volume":"26","author":"JY Hong","year":"2015","unstructured":"Hong JY, Yoon DH, Suh C, Huh J, Do IG, Sohn I, et al. EBV-positive diffuse large B-cell lymphoma in young adults: is this a distinct disease entity? Ann Oncol. 2015;26:548\u201355.","journal-title":"Ann Oncol"},{"key":"2994_CR6","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1002\/hon.2245","volume":"35","author":"A Okamoto","year":"2017","unstructured":"Okamoto A, Yanada M, Inaguma Y, Tokuda M, Morishima S, Kanie T, et al. The prognostic significance of EBV DNA load and EBER status in diagnostic specimens from diffuse large B-cell lymphoma patients. Hematol Oncol. 2017;35:87\u201393.","journal-title":"Hematol Oncol"},{"key":"2994_CR7","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1182\/blood-2016-01-643569","volume":"127","author":"SH Swerdlow","year":"2016","unstructured":"Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375\u201390.","journal-title":"Blood"},{"key":"2994_CR8","doi-asserted-by":"publisher","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","volume":"36","author":"R Alaggio","year":"2022","unstructured":"Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, Araujo IBO, Berti E, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022;36:1720\u201348.","journal-title":"Leukemia"},{"key":"2994_CR9","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1182\/blood.2022015851","volume":"140","author":"E Campo","year":"2022","unstructured":"Campo E, Jaffe ES, Cook JR, Quintanilla-Martinez L, Swerdlow SH, Anderson KC, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood. 2022;140:1229\u201353.","journal-title":"Blood"},{"key":"2994_CR10","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1182\/blood-2015-02-630632","volume":"126","author":"A Nicolae","year":"2015","unstructured":"Nicolae A, Pittaluga S, Abdullah S, Steinberg SM, Pham TA, Davies-Hill T, et al. EBV-positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment. Blood. 2015;126:863\u201372.","journal-title":"Blood"},{"key":"2994_CR11","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1002\/jmv.25381","volume":"91","author":"R Incrocci","year":"2019","unstructured":"Incrocci R, McAloon J, Montesano M, Bardahl J, Vagvala S, Stone A, et al. Epstein-Barr virus LMP2A utilizes Syk and PI3K to activate NF-kappaB in B-cell lymphomas to increase MIP-1alpha production. J Med Virol. 2019;91:845\u201355.","journal-title":"J Med Virol"},{"key":"2994_CR12","doi-asserted-by":"publisher","first-page":"195","DOI":"10.2353\/ajpath.2008.070845","volume":"173","author":"KR Baumforth","year":"2008","unstructured":"Baumforth KR, Birgersdotter A, Reynolds GM, Wei W, Kapatai G, Flavell JR, et al. Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin\u2019s lymphoma cells mediates Up-regulation of CCL20 and the migration of regulatory T cells. Am J Pathol. 2008;173:195\u2013204.","journal-title":"Am J Pathol"},{"key":"2994_CR13","doi-asserted-by":"publisher","first-page":"2715","DOI":"10.1038\/s41588-025-02353-5","volume":"57","author":"Y Dai","year":"2025","unstructured":"Dai Y, Kizhakeyil A, Chihara D, Li X, Liu Y, Sainz Z\u00fa\u00f1iga TP, et al. Multi-modal spatial characterization of tumor immune microenvironments identifies targetable inflammatory niches in diffuse large B cell lymphoma. Nat Genet. 2025;57:2715\u201327.","journal-title":"Nat Genet"},{"key":"2994_CR14","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1111\/ejh.13274","volume":"103","author":"C Keane","year":"2019","unstructured":"Keane C, Tobin J, Gunawardana J, Francis S, Gifford G, Gabrielli S, et al. The tumour microenvironment is immuno-tolerogenic and a principal determinant of patient outcome in EBV-positive diffuse large B-cell lymphoma. Eur J Haematol. 2019;103:200\u20137.","journal-title":"Eur J Haematol"},{"key":"2994_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-11052-z","volume":"7","author":"M Cohen","year":"2017","unstructured":"Cohen M, Vistarop AG, Huaman F, Narbaitz M, Metrebian F, De Matteo E, et al. Cytotoxic response against Epstein-Barr virus coexists with diffuse large B-cell lymphoma tolerogenic microenvironment: clinical features and survival impact. Sci Rep. 2017;7:10813.","journal-title":"Sci Rep"},{"key":"2994_CR16","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/1743-422X-11-94","volume":"11","author":"C Sueur","year":"2014","unstructured":"Sueur C, Lupo J, Mas P, Morand P, Boyer V. Difference in cytokine production and cell cycle progression induced by Epstein-Barr virus Lmp1 deletion variants in Kmh2, a Hodgkin lymphoma cell line. Virol J. 2014;11:94.","journal-title":"Virol J"},{"key":"2994_CR17","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1002\/ajh.26579","volume":"97","author":"L Malpica","year":"2022","unstructured":"Malpica L, Marques-Piubelli ML, Beltr\u00e1n BE, Ch\u00e1vez JC, Miranda RN, Castillo JJ. EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2022 update on diagnosis, risk-stratification, and management. Am J Hematol. 2022;97:951\u201365.","journal-title":"Am J Hematol"},{"key":"2994_CR18","doi-asserted-by":"publisher","first-page":"2816","DOI":"10.1002\/ijc.28942","volume":"135","author":"M Cohen","year":"2014","unstructured":"Cohen M, Narbaitz M, Metrebian F, De Matteo E, Preciado MV, Chabay PA. Epstein-Barr virus-positive diffuse large B-cell lymphoma association is not only restricted to elderly patients. Int J Cancer. 2014;135:2816\u201324.","journal-title":"Int J Cancer"},{"key":"2994_CR19","doi-asserted-by":"publisher","first-page":"3462","DOI":"10.1158\/1078-0432.CCR-13-0855","volume":"19","author":"BJ Chen","year":"2013","unstructured":"Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19:3462\u201373.","journal-title":"Clin Cancer Res"},{"key":"2994_CR20","doi-asserted-by":"crossref","unstructured":"Pei Y, Wong JHY, Robertson ES. Targeted therapies for Epstein-Barr virus-associated lymphomas. Cancers. 2020;12:2565.","DOI":"10.3390\/cancers12092565"},{"key":"2994_CR21","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.1002\/ijc.23392","volume":"122","author":"Y Mizukami","year":"2008","unstructured":"Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimura K, Sugai H, et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. Int J Cancer. 2008;122:2286\u201393.","journal-title":"Int J Cancer"},{"key":"2994_CR22","first-page":"2062","volume":"61","author":"CJ Kirk","year":"2001","unstructured":"Kirk CJ, Hartigan-O\u2019Connor D, Nickoloff BJ, Chamberlain JS, Giedlin M, Aukerman L, et al. T cell-dependent antitumor immunity mediated by secondary lymphoid tissue chemokine: augmentation of dendritic cell-based immunotherapy. Cancer Res. 2001;61:2062\u201370.","journal-title":"Cancer Res"},{"key":"2994_CR23","doi-asserted-by":"publisher","first-page":"2894","DOI":"10.1016\/j.vaccine.2003.12.021","volume":"22","author":"K Flanagan","year":"2004","unstructured":"Flanagan K, Glover RT, Horig H, Yang W, Kaufman HL. Local delivery of recombinant vaccinia virus expressing secondary lymphoid chemokine (SLC) results in a CD4 T-cell-dependent antitumor response. Vaccine. 2004;22:2894\u2013903.","journal-title":"Vaccine"},{"key":"2994_CR24","doi-asserted-by":"publisher","unstructured":"Leahy CI, Pugh MR, Hennessy A, Nikulina N, Dojcinov S, Niedobitek G, et al. The spatial landscape of infectious mononucleosis tonsils. Preprint at https:\/\/doi.org\/10.1101\/2025.10.09.681345 2025.","DOI":"10.1101\/2025.10.09.681345"},{"key":"2994_CR25","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1097\/PAP.0b013e318229bf08","volume":"18","author":"P Adam","year":"2011","unstructured":"Adam P, Bonzheim I, Fend F, Quintanilla-Martinez L. Epstein-Barr virus-positive diffuse large B-cell lymphomas of the elderly. Adv Anat Pathol. 2011;18:349\u201355.","journal-title":"Adv Anat Pathol"},{"key":"2994_CR26","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1002\/ajh.22252","volume":"87","author":"K Jones","year":"2012","unstructured":"Jones K, Nourse JP, Keane C, Crooks P, Gottlieb D, Ritchie DS, et al. Tumor-specific but not nonspecific cell-free circulating DNA can be used to monitor disease response in lymphoma. Am J Hematol. 2012;87:258\u201365.","journal-title":"Am J Hematol"},{"key":"2994_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/srep12168","volume":"5","author":"TX Lu","year":"2015","unstructured":"Lu TX, Liang JH, Miao Y, Fan L, Wang L, Qu XY, et al. Epstein-Barr virus-positive diffuse large B-cell lymphoma predicts poor outcome, regardless of age. Sci Rep. 2015;5:12168.","journal-title":"Sci Rep"},{"key":"2994_CR28","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1182\/blood-2007-01-067769","volume":"110","author":"S Park","year":"2007","unstructured":"Park S, Lee J, Ko YH, Han A, Jun HJ, Lee SC, et al. The impact of Epstein-Barr virus status on clinical outcome in diffuse large B-cell lymphoma. Blood. 2007;110:972\u20138.","journal-title":"Blood"},{"key":"2994_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-022-03554-w","volume":"20","author":"EE Abd El-Fattah","year":"2022","unstructured":"Abd El-Fattah EE. IDO\/kynurenine pathway in cancer: possible therapeutic approaches. J Transl Med. 2022;20:347.","journal-title":"J Transl Med"},{"key":"2994_CR30","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1084\/jem.20020121","volume":"196","author":"G Frumento","year":"2002","unstructured":"Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196:459\u201368.","journal-title":"J Exp Med"},{"key":"2994_CR31","doi-asserted-by":"publisher","first-page":"S17","DOI":"10.1097\/01.tp.0000269199.16209.22","volume":"84","author":"ML Belladonna","year":"2007","unstructured":"Belladonna ML, Puccetti P, Orabona C, Fallarino F, Vacca C, Volpi C, et al. Immunosuppression via tryptophan catabolism: the role of kynurenine pathway enzymes. Transplantation. 2007;84:S17\u201320.","journal-title":"Transplantation"},{"key":"2994_CR32","doi-asserted-by":"publisher","first-page":"18176","DOI":"10.1074\/jbc.M116.715854","volume":"291","author":"ZZ Mei","year":"2016","unstructured":"Mei ZZ, Chen XY, Hu SW, Wang N, Ou XL, Wang J, et al. Kelch-like protein 21 (KLHL21) targets IkappaB kinase-beta to regulate nuclear factor kappa-light chain enhancer of activated b cells (NF-kappaB) signaling negatively. J Biol Chem. 2016;291:18176\u201389.","journal-title":"J Biol Chem"},{"key":"2994_CR33","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-016-0729-9","volume":"33","author":"F Zhu","year":"2016","unstructured":"Zhu F, Li X, Chen S, Zeng Q, Zhao Y, Luo F. Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma. Med Oncol. 2016;33:17.","journal-title":"Med Oncol"},{"key":"2994_CR34","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1126\/science.ade2292","volume":"381","author":"R Bill","year":"2023","unstructured":"Bill R, Wirapati P, Messemaker M, Roh W, Zitti B, Duval F, et al. CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers. Science. 2023;381:515\u201324.","journal-title":"Science"},{"key":"2994_CR35","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1038\/modpathol.2012.52","volume":"25","author":"S Montes-Moreno","year":"2012","unstructured":"Montes-Moreno S, Odqvist L, D\u00edaz-P\u00e9rez JA, L\u00f3pez AB, de Villambrosia SG, Mazorra F, et al. EBV-positive diffuse large B-cell lymphoma of the elderly is an aggressive post-germinal center B-cell neoplasm characterized by prominent nuclear factor-kB activation. Mod Pathol. 2012;25:968\u201382.","journal-title":"Mod Pathol"},{"key":"2994_CR36","doi-asserted-by":"publisher","first-page":"32925","DOI":"10.18632\/oncotarget.9076","volume":"7","author":"S Derks","year":"2016","unstructured":"Derks S, Liao X, Chiaravalli AM, Xu X, Camargo MC, Solcia E, et al. Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers. Oncotarget. 2016;7:32925\u201332.","journal-title":"Oncotarget"},{"key":"2994_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21043-4","volume":"12","author":"Y Liu","year":"2021","unstructured":"Liu Y, He S, Wang XL, Peng W, Chen QY, Chi DM, et al. Tumour heterogeneity and intercellular networks of nasopharyngeal carcinoma at single cell resolution. Nat Commun. 2021;12:741.","journal-title":"Nat Commun"},{"key":"2994_CR38","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s12672-022-00479-0","volume":"13","author":"A Lima","year":"2022","unstructured":"Lima A, Sousa H, Medeiros R, Nobre A, Machado M. PD-L1 expression in EBV-associated gastric cancer: a systematic review and meta-analysis. Discov Oncol. 2022;13:19.","journal-title":"Discov Oncol"},{"key":"2994_CR39","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1186\/s13045-016-0341-7","volume":"9","author":"XW Bi","year":"2016","unstructured":"Bi XW, Wang H, Zhang WW, Wang JH, Liu WJ, Xia ZJ, et al. PD-L1 is upregulated by EBV-driven LMP1 through the NF-kappaB pathway and correlates with poor prognosis in natural killer\/T-cell lymphoma. J Hematol Oncol. 2016;9:109.","journal-title":"J Hematol Oncol"},{"key":"2994_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2435-y","volume":"11","author":"R Huang","year":"2020","unstructured":"Huang R, Wang S, Wang N, Zheng Y, Zhou J, Yang B, et al. CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating beta-catenin\/STAT3 signaling. Cell Death Dis. 2020;11:234.","journal-title":"Cell Death Dis"},{"key":"2994_CR41","doi-asserted-by":"publisher","first-page":"1882","DOI":"10.1016\/j.biocel.2003.10.019","volume":"36","author":"M Maurer","year":"2004","unstructured":"Maurer M, von Stebut E. Macrophage inflammatory protein-1. Int J Biochem Cell Biol. 2004;36:1882\u20136.","journal-title":"Int J Biochem Cell Biol"},{"key":"2994_CR42","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, et al. Differential immunogenicity of Epstein-Barr virus latent-cycle proteins for human CD4(+) T-helper 1 responses. J Virol. 2001;75:8649\u201359.","journal-title":"J Virol"},{"key":"2994_CR43","doi-asserted-by":"publisher","unstructured":"Fennell \u00c9, Brandon C, Bo\u00dfelmann S, Ryan SE, Singh A, Hennessy A, et al. CellMAPS: a no-code model-based customisable multiplex image analysis workflow. Preprint at https:\/\/doi.org\/10.1101\/2025.10.07.680848 2025.","DOI":"10.1101\/2025.10.07.680848"},{"key":"2994_CR44","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1038\/s41587-021-01094-0","volume":"40","author":"NF Greenwald","year":"2022","unstructured":"Greenwald NF, Miller G, Moen E, Kong A, Kagel A, Dougherty T, et al. Whole-cell segmentation of tissue images with human-level performance using large-scale data annotation and deep learning. Nat Biotechnol. 2022;40:555\u201365.","journal-title":"Nat Biotechnol"},{"key":"2994_CR45","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1016\/j.celrep.2018.07.003","volume":"24","author":"Z Hu","year":"2018","unstructured":"Hu Z, Jujjavarapu C, Hughey JJ, Andorf S, Lee HC, Gherardini PF, et al. MetaCyto: a tool for automated meta-analysis of mass and flow cytometry data. Cell Rep. 2018;24:1377\u201388.","journal-title":"Cell Rep"},{"key":"2994_CR46","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1016\/j.cell.2020.07.005","volume":"182","author":"CM Schurch","year":"2020","unstructured":"Schurch CM, Bhate SS, Barlow GL, Phillips DJ, Noti L, Zlobec I, et al. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. Cell. 2020;182:1341\u201359 e1319.","journal-title":"Cell"},{"key":"2994_CR47","unstructured":"Andrews S. FastQC: a quality control tool for high-throughput sequence data. 2010."},{"key":"2994_CR48","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15\u201321.","journal-title":"Bioinformatics"},{"key":"2994_CR49","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders S, Pyl PT, Huber W. HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166\u20139.","journal-title":"Bioinformatics"},{"key":"2994_CR50","doi-asserted-by":"publisher","first-page":"2943","DOI":"10.1093\/bioinformatics\/btac166","volume":"38","author":"GH Putri","year":"2022","unstructured":"Putri GH, Anders S, Pyl PT, Pimanda JE, Zanini F. Analysing high-throughput sequencing data in Python with HTSeq 2.0. Bioinformatics. 2022;38:2943\u20135.","journal-title":"Bioinformatics"},{"key":"2994_CR51","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.","journal-title":"Genome Biol"},{"key":"2994_CR52","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/j.cell.2017.09.027","volume":"171","author":"A Reddy","year":"2017","unstructured":"Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, et al. Genetic and functional drivers of diffuse large B-cell lymphoma. Cell. 2017;171:481\u201394 e415.","journal-title":"Cell"},{"key":"2994_CR53","doi-asserted-by":"crossref","unstructured":"Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE. 2012;7:e51862.","DOI":"10.1371\/journal.pone.0051862"},{"key":"2994_CR54","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545\u201350.","journal-title":"Proc Natl Acad Sci USA"},{"key":"2994_CR55","doi-asserted-by":"publisher","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","volume":"32","author":"Z Gu","year":"2016","unstructured":"Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32:2847\u20139.","journal-title":"Bioinformatics"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02994-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02994-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02994-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T18:17:01Z","timestamp":1785521821000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02994-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":55,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["2994"],"URL":"https:\/\/doi.org\/10.1038\/s41375-026-02994-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-8642719\/v1","asserted-by":"object"}]},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,10]]},"assertion":[{"value":"19 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}