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Open Access 01-02-2024 | Epstein-Barr Virus | Research

Presence of Epstein–Barr virus (EBV) antigens detected by sensitive methods has no influence on local immune environment in diffuse large B cell lymphoma

Authors: T. Mangiaterra, R. Alonso-Alonso, A. Rabinovich, M. De Dios Soler, L. Galluzzo, M. Soria, S. Colli, E. De Matteo, S. M. Rodriguez Pinilla, P. Chabay

Published in: Cancer Immunology, Immunotherapy | Issue 2/2024

Abstract

EBV+ diffuse large B cell lymphoma (DLBCL) not otherwise specified (NOS) is a new entity confirmed by the World Health Organization (WHO) in 2017. In this new entity, the virus may contribute to a tolerogenic microenvironment. Traces of the virus have been described in DLBCL with more sensitive methods, in cases that were originally diagnosed as negative. The aim of this study was to analyze the expression of immune response genes in the tumor microenvironment to disclose the role of the virus and its traces in DLBCL. In 48 DLBCL cases, the expression of immune response genes and the presence of molecules that induce tolerance, such as TIM3, LAG3 and PDL1 by immunohistochemistry (IHC), were studied. To broaden the study of the microenvironment, tumor-associated macrophages (TMAs) were also explored. No significant differences were observed in the expression of immune response genes in the EBV+ DLBCL and those cases that were EBV− DLBCL but that exhibited viral traces, assessed by ViewRNA assay. Only the EBV+ DLBCL cases displayed a significantly higher increase in the expression of CD8 and cytotoxic T cells detected by gene expression analysis, and of PDL1 in tumor cells and in the expression of CD68 in the tumor microenvironment detected by IHC, not observed in those cases with viral traces. The increase in CD8 and cytotoxic T cells, PDL1 and CD68 markers only in EBV+ DLBCL may indicate that traces of viral infection might not have influence in immune response markers.

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Chen CJ, Hsu WL, Yang HI, Lee MH, Chen HC, Chien YC, You SL (2014) Epidemiology of virus infection and human cancer. In: Chang M, Jeang KT (eds) Viruses and human cancer recent. Results in cancer research, vol 193. Springer, Berlin

Shannon-Lowe C, Rickinson A, Bell A (2017) Epstein-Barr virus-associated lymphomas. Philos Trans R Soc Lond B Biol Sci 372:20160271. https://doi.org/10.1098/rstb.2016.0271CrossRefPubMedPubMedCentral

Mundo L, Del Porro L, Granai M, Siciliano MC, Mancini V, Santi R, Marcar L, Vrzalikova K, Vergoni F, Di Stefano G, Schiavoni G, Segreto G, Onyango N, Nyagol JA, Amato T, Bellan C, Anagnostopoulos I, Falini B, Leoncini L, Lazzi S (2020) Frequent traces of EBV infection in Hodgkin and non-Hodgkin lymphomas classified as EBV−negative by routine methods: expanding the landscape of EBV−related lymphomas. Mod Pathol 33:2407–2421. https://doi.org/10.1038/s41379-020-0575-3CrossRefPubMedPubMedCentral

Mundo L, Ambrosio MR, Picciolini M, Lo Bello G, Gazaneo S, Del Porro L, Lazzi S, Navari M, Onyango N, Granai M, Bellan C, De Falco G, Gibellini D, Piccaluga PP, Leoncini L (2017) Unveiling another missing piece in EBV−driven lymphomagenesis: EBV−encoded microRNAs expression in EBER-negative Burkitt lymphoma cases. Front Microbiol 8(229):2017. https://doi.org/10.3389/fmicb.2017.00229.eCollectionCrossRef

Ambinder R (2000) Gammaherpesviruses and “Hit-and-Run” oncogenesis. Am J Pathol 156:1–3. https://doi.org/10.1016/S0002-9440(10)64697-4CrossRefPubMedPubMedCentral

Mangiaterra TS, De Dios SM, Oviedo N, Colli S, Preciado MV, Soria M, Galluzo L, Matteo ED, Chabay P (2023) Presence of EBV antigens detected by a sensitive method in pediatric and adult Diffuse Large B-cell lymphomas. Int J Cancer 153:1043–1050. https://doi.org/10.1002/ijc.34623CrossRefPubMed

Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES (2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasm. Blood 127:2375–2390. https://doi.org/10.1182/blood-2016-01-643569CrossRefPubMedPubMedCentral

Nicolae A, Pittaluga S, Abdullah S, Steinberg S, Pham T, Davies-Hill T, Xi L, Raffeld M, Jaffe E (2015) EBV−positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment. Blood 126(7):863–872. https://doi.org/10.1182/blood-2015-02-630632CrossRefPubMedPubMedCentral

Scott DW, Gascoyne RD (2014) The tumour microenvironment in B cell lymphomas. Nat Rev Cancer 14:517–534. https://doi.org/10.1038/nrc3774CrossRefPubMed

10.

Keane C, Tobin J, Gunawardana J, Francis S, Gifford G, Gabrielli S, Gill A, Stevenson W, Talaulikar D, Gould C, Jain S, Birch S, Hertzberg M, Gandhi MK (2019) The tumour microenvironment is immuno-tolerogenic and a principal determinant of patient outcome in EBV−positive diffuse large B-cell lymphoma. Eur J Haematol 103:200–207. https://doi.org/10.1111/ejh.13274CrossRefPubMedPubMedCentral

11.

Ma J, Pang X, Li J, Zhang W, Cui W (2022) The immune checkpoint expression in the tumor immune microenvironment of DLBCL: clinicopathologic features and prognosis. Front Oncol 12:1069378. https://doi.org/10.3389/fonc.2022.1069378CrossRefPubMedPubMedCentral

12.

Chen BJ, Dashnamoorthy R, Galera P, Makarenko V, Chang H, Ghosh S, Evens AM (2019) The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma. Oncotarget 10:2030–2040. https://doi.org/10.18632/oncotarget.26771CrossRefPubMedPubMedCentral

13.

Hajifathali A, Parkhideh S, Kazemi MH, Chegeni R, Roshandel E, Gholizadeh M (2020) Immune checkpoints in hematologic malignancies: What made the immune cells and clinicians exhausted! J Cell Physiol 235:9080–9097. https://doi.org/10.1002/jcp.29769CrossRefPubMed

14.

Kiyasu J, Miyoshi H, Hirata A, Arakawa F, Ichikawa A, Niino D, Sugita Y, Yufu Y, Choi I, Abe Y, Uike N, Nagafuji K, Okamura T, Akashi K, Takayanagi R, Shiratsuchi M, Ohshima K (2015) Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood 126:2193–2201. https://doi.org/10.1182/blood-2015-02-629600CrossRefPubMedPubMedCentral

15.

Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22:231–237. https://doi.org/10.1016/j.coi.2010.01.009. (PMID: 20144856)CrossRefPubMed

16.

Riihijärvi S, Fiskvik I, Taskinen M, Vajavaara H, Tikkala M, Yri O, Karjalainen-Lindsberg L, Delabie J, Smeland E, Holte H, Leppä S (2015) Prognostic influence of macrophages in patients with diffuse large B-cell lymphoma: a correlative study from a Nordic phase II trial. Haematologica 100:238–245. https://doi.org/10.3324/haematol.2014.113472CrossRefPubMedPubMedCentral

17.

Cioroianu AI, Stinga PI, Sticlaru L, Cioplea MD, Nichita L, Popp C, Staniceanu F (2019) Tumor Microenvironment in diffuse large B-cell lymphoma: role and prognosis. Anal Cell Pathol (Amst) 2019:8586354. https://doi.org/10.1155/2019/8586354CrossRefPubMed

18.

Rodríguez M, Alonso-Alonso R, Fernández-Miranda I, Mondéjar R, Cereceda L, Tráscasa Á, Antonio-Da Conceiçao A, Borregón J, Gato L, Tomás-Roca L, Bárcena C, Iglesias B, Climent F, González-Barca E, Camacho FI, Mayordomo É, Olmedilla G, Gómez-Prieto P, Castro Y, Serrano-López J, Sánchez-García J, Montes-Moreno S, García-Cosío M, Martín-Acosta P, García JF, Planelles M, Quero C, Provencio M, Mahíllo-Fernández I, Rodríguez-Pinilla SM, Derenzini E, Pileri S, Sánchez-Beato M, Córdoba R, Piris MA (2022) An integrated prognostic model for diffuse large B-cell lymphoma treated with immunochemotherapy. E J Haem 3:722–733. https://doi.org/10.1002/jha2.457CrossRef

19.

Rodríguez M, Alonso-Alonso R, Tomás-Roca L, Rodríguez-Pinilla SM, Manso-Alonso R, Cereceda L, Borregón J, Villaescusa T, Córdoba R, Sánchez-Beato M, Fernández-Miranda I, Betancor I, Bárcena C, García JF, Mollejo M, García-Cosio M, Martin-Acosta P, Climent F, Caballero D, de la Fuente L, Mínguez P, Kessler L, Scholz C, Gualberto A, Mondéjar R, Piris MA (2021) Peripheral T-cell lymphoma: molecular profiling recognizes subclasses and identifies prognostic markers. Blood Adv 5:5588–5598. https://doi.org/10.1182/bloodadvances.2021005171CrossRefPubMedPubMedCentral

20.

Chabay PA, Preciado MV (2013) EBV primary infection in childhood and its relation to B-cell lymphoma development: a mini-review from a developing region. Int J Cancer 133:1286–1292. https://doi.org/10.1002/ijc.27858CrossRefPubMed

21.

Cohen M, De Matteo E, Narbaitz M, Carreño FA, Preciado MV, Chabay PA (2013) Epstein-Barr virus presence in pediatric diffuse large B-cell lymphoma reveals a particular association and latency patterns: analysis of viral role in tumor microenvironment. Int J Cancer 132:1572–1580. https://doi.org/10.1002/ijc.27845CrossRefPubMed

22.

R Core Team (2022) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/.

23.

Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Müller-Hermelink HK, Campo E, Braziel RM, Jaffe ES, Pan Z, Farinha P, Smith LM, Falini B, Banham AH, Rosenwald A, Staudt LM, Connors JM, Armitage JO, Chan WC (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275–282. https://doi.org/10.1182/blood-2003-05-1545CrossRefPubMed

24.

Cohen M, Narbaitz M, Metrebian F, De Matteo E, Preciado MV, Chabay PA (2014) Epstein-Barr virus-positive diffuse large B-cell lymphoma association is not only restricted to elderly patients. Int J Cancer 135:2816–2824. https://doi.org/10.1002/ijc.28942CrossRefPubMed

25.

Moyano A, Ferressini Gerpe NM, De Matteo E, Preciado MV, Chabay PA (2022) M1 macrophage polarization prevails in Epstein-Barr virus-infected children in an immunoregulatory environment. J Virol 96:e0143421. https://doi.org/10.1128/JVI.01434-21CrossRefPubMed

26.

Siciliano MC, Tornambè S, Cevenini G, Sorrentino E, Granai M, Giovannoni G, Marrelli D, Biviano I, Roviello F, Yoshiyama H, Leoncini L, Lazzi S, Mundo L (2022) EBV persistence in gastric cancer cases conventionally classified as EBER-ISH negative. Infect Agent Cancer 17:57. https://doi.org/10.1186/s13027-022-00469-5CrossRefPubMedPubMedCentral

27.

Cohen M, Vistarop AG, Huaman F, Narbaitz M, Metrebian F, De Matteo E, Preciado MV, Chabay PA (2017) Cytotoxic response against Epstein Barr virus coexists with diffuse large B-cell lymphoma tolerogenic microenvironment: clinical features and survival impact. Sci Rep 7:10813. https://doi.org/10.1038/s41598-017-11052-zADSCrossRefPubMedPubMedCentral

28.

Hu LY, Xu XL, Rao HL, Chen J, Lai RC, Huang HQ, Jiang WQ, Lin TY, Xia ZJ, Cai QQ (2017) Expression and clinical value of programmed cell death-ligand 1 (PD-L1) in diffuse large B cell lymphoma: a retrospective study. Chin J Cancer 36:94. https://doi.org/10.1186/s40880-017-0262-zCrossRefPubMedPubMedCentral

29.

Kwon D, Kim S, Kim PJ, Go H, Nam SJ, Paik JH, Kim YA, Kim TM, Heo DS, Kim CW, Jeon YK (2016) Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas. Histopathology 68:1079–1089. https://doi.org/10.1111/his.12882CrossRefPubMed

30.

Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML, Yu H, Fletcher CD, Freeman GJ, Shipp MA, Rodig SJ (2013) PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 19:3462–3473. https://doi.org/10.1158/1078-0432.CCR-13-0855CrossRefPubMedPubMedCentral

31.

Kataoka K, Miyoshi H, Sakata S, Dobashi A, Couronné L, Kogure Y, Sato Y, Nishida K, Gion Y, Shiraishi Y, Tanaka H, Chiba K, Watatani Y, Kakiuchi N, Shiozawa Y, Yoshizato T, Yoshida K, Makishima H, Sanada M, Onozawa M, Teshima T, Yoshiki Y, Ishida T, Suzuki K, Shimada K, Tomita A, Kato M, Ota Y, Izutsu K, Demachi-Okamura A, Akatsuka Y, Miyano S, Yoshino T, Gaulard P, Hermine O, Takeuchi K, Ohshima K, Ogawa S (2019) Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas. Leukemia 33:1687–1699. https://doi.org/10.1038/s41375-019-0380-5CrossRefPubMedPubMedCentral

32.

Cristino AS, Nourse J, West RA, Sabdia MB, Law SC, Gunawardana J, Vari F, Mujaj S, Thillaiyampalam G, Snell C, Gough M, Keane C, Gandhi MK (2019) EBV microRNA-BHRF1-2-5p targets the 3’UTR of immune checkpoint ligands PD-L1 and PD-L2. Blood 134:2261–2270. https://doi.org/10.1182/blood.2019000889CrossRefPubMedPubMedCentral

33.

Anastasiadou E, Stroopinsky D, Alimperti S, Jiao AL, Pyzer AR, Cippitelli C, Pepe G, Severa M, Rosenblatt J, Etna MP, Rieger S, Kempkes B, Coccia EM, Sui SJH, Chen CS, Uccini S, Avigan D, Faggioni A, Trivedi P, Slack FJ (2019) Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas. Leukemia 33:132–147. https://doi.org/10.1038/s41375-018-0178-xCrossRefPubMed

34.

Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51. https://doi.org/10.1016/j.cell.2010.03.014CrossRefPubMedPubMedCentral

35.

Granai M, Lazzi S, Mancini V, Akarca A, Santi R, Vergoni F, Sorrentino E, Guazzo R, Mundo L, Cevenini G, Tripodo C, Di Stefano G, Puccini B, Ponzoni M, Sabattini E, Agostinelli C, Bassüllü N, Tecimer T, Demiroz AS, Mnango L, Dirnhofer S, Quintanilla-Martinez L, Marafioti T, Fend F, Leoncini L (2022) Burkitt lymphoma with a granulomatous reaction: an M1/Th1-polarised microenvironment is associated with controlled growth and spontaneous regression. Histopathology 80:430–442. https://doi.org/10.1111/his.14391CrossRefPubMed

36.

Barros MH, Hassan R, Niedobitek G (2012) Tumor-associated macrophages in pediatric classical Hodgkin lymphoma: association with Epstein-Barr virus, lymphocyte subsets, and prognostic impact. Clin Cancer Res 18:3762–3771. https://doi.org/10.1158/1078-0432.CCR-12-0129CrossRefPubMed

37.

Jimenez O, Barros MH, De Matteo E, Garcia Lombardi M, Preciado MV, Niedobitek G, Chabay P (2019) M1-like macrophage polarization prevails in young children with classic Hodgkin Lymphoma from Argentina. Sci Rep 9:12687. https://doi.org/10.1038/s41598-019-49015-1ADSCrossRefPubMedPubMedCentral

38.

Wang J, Gao K, Lei W, Dong L, Xuan Q, Feng M, Wang J, Ye X, Jin T, Zhang Z, Zhang Q (2017) Lymphocyte-to-monocyte ratio is associated with prognosis of diffuse large B-cell lymphoma: correlation with CD163 positive M2 type tumor-associated macrophages, not PD-1 positive tumor-infiltrating lymphocytes. Oncotarget 8:5414–5425. https://doi.org/10.18632/oncotarget.14289CrossRefPubMed

39.

Poles WA, Nishi EE, de Oliveira MB, Eugênio AIP, de Andrade TA, Campos AHFM, de Campos Jr. RR, Vassallo J, Alves AC, Scapulatempo Neto C, Paes RAP, Landman G, Zerbini MCN, Colleoni GWB (2019) Targeting the polarization of tumor-associated macrophages and modulating mir-155 expression might be a new approach to treat diffuse large B-cell lymphoma of the elderly. Cancer Immunol Immunother 68:269–282. https://doi.org/10.1007/s00262-018-2273-2CrossRefPubMed

Title: Presence of Epstein–Barr virus (EBV) antigens detected by sensitive methods has no influence on local immune environment in diffuse large B cell lymphoma
Authors: T. Mangiaterra
R. Alonso-Alonso
A. Rabinovich
M. De Dios Soler
L. Galluzzo
M. Soria
S. Colli
E. De Matteo
S. M. Rodriguez Pinilla
P. Chabay
Publication date: 01-02-2024
Publisher: Springer Berlin Heidelberg
Keywords: Epstein-Barr Virus
Diffuse Large B-Cell Lymphoma
Diffuse Large B-Cell Lymphoma
Published in: Cancer Immunology, Immunotherapy / Issue 2/2024
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-023-03617-x

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