{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T03:46:53Z","timestamp":1790480813333,"version":"4.1.0"},"reference-count":97,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T00:00:00Z","timestamp":1646352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"S\u00e3o Paulo Research Foundation","doi-asserted-by":"publisher","award":["2019\/14324-9"],"award-info":[{"award-number":["2019\/14324-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The Epstein-Barr Virus (EBV) is a gammaherpesvirus involved in the etiopathogenesis of a variety of human cancers, mostly of lymphoid and epithelial origin. The EBV infection participates in both cell transformation and tumor progression, also playing an important role in subverting immune responses against cancers. The homeostasis of the immune system is tightly regulated by inhibitory mechanisms affecting key immune effectors, such as T lymphocytes and NK cells. Collectively known as immune checkpoints, these mechanisms rely on a set of cellular receptors and ligands. These molecules may be candidate targets for immune checkpoints blockade\u2014an emergent and promising modality of immunotherapy already proven to be valuable for a variety of human cancers. The EBV was lately suspected to interfere with the expression of immune checkpoint molecules, notably PD-1 and its ligands, found to be overexpressed in cases of Hodgkin lymphoma, nasopharyngeal, and gastric adenocarcinomas associated with the viral infection. Even though there is compelling evidence showing that the EBV interferes with other immune checkpoint regulators (e.g., CTLA-4, LAG-3, TIM-3, and VISTA), the published data are still scarce. Herein, we discuss the current state of the knowledge on how the EBV interferes with the activity of immune checkpoints regulators, as well as its implications considering the immune checkpoints blockade for clinical management of the EBV-associated malignancies, notably lymphomas.<\/jats:p>","DOI":"10.3390\/biom12030397","type":"journal-article","created":{"date-parts":[[2022,3,6]],"date-time":"2022-03-06T20:35:50Z","timestamp":1646598950000},"page":"397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The Epstein-Barr Virus Hacks Immune Checkpoints: Evidence and Consequences for Lymphoproliferative Disorders and Cancers"],"prefix":"10.3390","volume":"12","author":[{"given":"Alison Felipe Bordini","family":"Biggi","sequence":"first","affiliation":[{"name":"Biosciences Institute of Botucatu, S\u00e3o Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5562-9648","authenticated-orcid":false,"given":"Deilson","family":"Elgui de Oliveira","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical School, S\u00e3o Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil"},{"name":"ViriCan, Institute for Biotechnology (IBTEC), S\u00e3o Paulo State University (UNESP), Botucatu 18607-440, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1002\/ijc.31937","article-title":"Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods","volume":"144","author":"Ferlay","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e180","DOI":"10.1016\/S2214-109X(19)30488-7","article-title":"Global burden of cancer attributable to infections in 2018: A worldwide incidence analysis","volume":"8","author":"Georges","year":"2020","journal-title":"Lancet Glob. Health"},{"key":"ref_4","unstructured":"IARC (2011). IARC Working Group on the Evaluation of Carcinogenic Risks to Humans A Review of Human Carcinogens\u2014Part B: Biological Agents. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, International Agency for Research on Cancer (IARC)."},{"key":"ref_5","unstructured":"IARC (2012). IARC. IARC Working Group on the Evaluation of Carcinogenic Risk to Humans Biological Agents\u2014Epstein-Barr Virus. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, International Agency for Research on Cancer."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/nrc.2016.92","article-title":"Epstein-Barr virus: More than 50 years old and still providing surprises","volume":"16","author":"Young","year":"2016","journal-title":"Nat. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"713","DOI":"10.3389\/fonc.2019.00713","article-title":"The Global Landscape of EBV-Associated Tumors","volume":"9","author":"Rickinson","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10040","DOI":"10.1128\/JVI.79.15.10040-10052.2005","article-title":"Interferon Regulatory Factor 7 Is Negatively Regulated by the Epstein-Barr Virus Immediate-Early Gene, BZLF-1","volume":"79","author":"Hahn","year":"2005","journal-title":"J. Virol."},{"key":"ref_9","first-page":"1694","article-title":"EBV Lytic-Phase Protein BGLF5 Contributes to TLR9 Downregulation during Productive Infection","volume":"186","author":"Griffin","year":"2010","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1099\/jgv.0.000021","article-title":"Silencing the shutoff protein of Epstein-Barr virus in productively infected B cells points to (innate) targets for immune evasion","volume":"96","author":"Gram","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Jochum, S., Moosmann, A., Lang, S., Hammerschmidt, W., and Zeidler, R. (2012). The EBV Immunoevasins vIL-10 and BNLF2a Protect Newly Infected B Cells from Immune Recognition and Elimination. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002704"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zuo, J., Thomas, W.A., Haigh, T.A., Fitzsimmons, L., Long, H.M., Hislop, A.D., Taylor, G.S., and Rowe, M. (2011). Epstein-Barr Virus Evades CD4+ T Cell Responses in Lytic Cycle through BZLF1-mediated Downregulation of CD74 and the Cooperation of vBcl-2. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002455"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1128\/JVI.01946-07","article-title":"The DNase of Gammaherpesviruses Impairs Recognition by Virus-Specific CD8 + T Cells through an Additional Host Shutoff Function","volume":"82","author":"Zuo","year":"2008","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3389\/fonc.2018.00265","article-title":"Epstein-Barr Virus-Associated Malignancies: Roles of Viral Oncoproteins in Carcinogenesis","volume":"8","author":"Malki","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.canlet.2020.11.019","article-title":"Epstein-Barr virus microRNAs in the pathogenesis of human cancers","volume":"499","author":"Caetano","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer: The Next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16085","DOI":"10.1074\/jbc.274.23.16085","article-title":"Activation of the p38 Mitogen-activated Protein Kinase Pathway by Epstein-Barr Virus-encoded Latent Membrane Protein 1 Coregulates Interleukin-6 and Interleukin-8 Production","volume":"274","author":"Eliopoulos","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1126\/science.1096781","article-title":"Identification of Virus-Encoded MicroRN-As","volume":"304","author":"Pfeffer","year":"2004","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1158\/0008-5472.CAN-07-5126","article-title":"EBV MicroRNAs in Primary Lymphomas and Targeting of CXCL-11 by ebv-mir-BHRF1-3","volume":"68","author":"Xia","year":"2008","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"M\u00fcnz, C. (2021). Co-Stimulatory Molecules during Immune Control of Epstein Barr Virus Infection. Biomolecules, 12.","DOI":"10.3389\/fmicb.2021.657387"},{"key":"ref_21","unstructured":"Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., and Thiele, J. (2017). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, International Agency for Research on Cancer. [4th ed.]."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.3389\/fimmu.2018.02469","article-title":"Regulation of the Germinal Center Response","volume":"9","author":"Stebegg","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S1074-7613(00)00049-2","article-title":"The Expression Pattern of Epstein-Barr Virus Latent Genes In Vivo Is Dependent upon the Differentiation Stage of the Infected B Cell","volume":"13","author":"Babcock","year":"2000","journal-title":"Immunity"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1056\/NEJMra032015","article-title":"Persistence of the Epstein-Barr Virus and the Origins of Associated Lymphomas","volume":"350","author":"Gross","year":"2004","journal-title":"New Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3322\/caac.21438","article-title":"Hodgkin lymphoma: A review and update on recent progress","volume":"68","author":"Shanbhag","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Carbone, A., and Gloghini, A. (2018). Epstein Barr Virus-Associated Hodgkin Lymphoma. Cancers, 10.","DOI":"10.3390\/cancers10060163"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.anndiagpath.2014.03.007","article-title":"Epstein-Barr virus\u2013positive nodular lymphocyte predominant Hodgkin lymphoma","volume":"18","author":"Wang","year":"2014","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1097\/PAS.0000000000000107","article-title":"EBV May Be Expressed in the LP Cells of Nodular Lymphocyte\u2013predominant Hodgkin Lymphoma (NLPHL) in Both Children and Adults","volume":"38","author":"Huppmann","year":"2014","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9337","DOI":"10.1073\/pnas.94.17.9337","article-title":"Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells","volume":"94","author":"Braeuninger","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1182\/blood.V95.4.1443.004k55_1443_1450","article-title":"Hodgkin and Reed-Sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription","volume":"95","author":"Marafioti","year":"2000","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7837","DOI":"10.1073\/pnas.79.24.7837","article-title":"Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells","volume":"79","author":"Taub","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1002\/ajh.25112","article-title":"EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2018 update on diagnosis, risk-stratification and management","volume":"93","author":"Castillo","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1053\/j.semdp.2017.04.003","article-title":"Human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) related lymphomas, pathology view point","volume":"34","author":"Fend","year":"2017","journal-title":"Semin. Diagn. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.canlet.2011.02.007","article-title":"HIV, EBV and KSHV: Viral Cooperation in the Pathogenesis of Human Malignancies","volume":"305","year":"2011","journal-title":"Cancer Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1007\/s11899-012-0136-z","article-title":"Epstein-Barr Virus and the Pathogenesis of T and NK Lymphoma: A Mystery Unsolved","volume":"7","author":"George","year":"2012","journal-title":"Curr. Hematol. Malign- Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7604","DOI":"10.1200\/JCO.2005.02.6310","article-title":"Epstein-Barr Virus as a Marker of Survival after Hodgkin\u2019s Lymphoma: A Population-Based Study","volume":"23","author":"Keegan","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1007\/s00277-012-1464-8","article-title":"Impact of the Epstein-Barr virus positivity on Hodgkin\u2019s lymphoma in a large cohort from a single institute in Korea","volume":"91","author":"Koh","year":"2012","journal-title":"Ann. Hematol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12168","DOI":"10.1038\/srep12168","article-title":"Epstein-Barr virus positive diffuse large B-cell lymphoma predict poor outcome, regardless of the age","volume":"5","author":"Lu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1111\/ejh.13274","article-title":"The tumour microenvironment is immuno-tolerogenic and a principal determinant of patient outcome in EBV-positive diffuse large B-cell lymphoma","volume":"103","author":"Keane","year":"2019","journal-title":"Eur. J. Haematol."},{"key":"ref_40","first-page":"4472","article-title":"T-Cell Proliferation Involving the CD28 Pathway Is Associated with Cyclosporine-Resistant Interleukin 2 Gene Expression","volume":"7","author":"June","year":"1987","journal-title":"Mol. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1146\/annurev.iy.07.040189.002305","article-title":"Clonal Expansion Versus Functional Clonal Inactivation: A Costimulatory Signalling Pathway Determines the Outcome of T Cell Antigen Receptor Occupancy","volume":"7","author":"Mueller","year":"1989","journal-title":"Annu. Rev. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/s41577-020-0296-3","article-title":"Modulation of regulatory T cell function and stability by co-inhibitory receptors","volume":"20","author":"Lucca","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.immuni.2007.05.016","article-title":"Programmed Death-1 Ligand 1 Interacts Specifically with the B7-1 Costimulatory Molecule to Inhibit T Cell Responses","volume":"27","author":"Butte","year":"2007","journal-title":"Immunity"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nri.2017.108","article-title":"The diverse functions of the PD1 inhibitory pathway","volume":"18","author":"Sharpe","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.4049\/jimmunol.155.3.1032","article-title":"Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4","volume":"155","author":"Kearney","year":"1995","journal-title":"J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/1074-7613(95)90125-6","article-title":"Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4","volume":"3","author":"Tivol","year":"1995","journal-title":"Immunity"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1097\/COC.0000000000000239","article-title":"CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition","volume":"39","author":"Buchbinder","year":"2016","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.3389\/fimmu.2018.02737","article-title":"CTLA-4 and PD-1 Control of T-Cell Motility and Migration: Implications for Tumor Immunotherapy","volume":"9","author":"Rudd","year":"2018","journal-title":"Front Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3268","DOI":"10.1182\/blood-2010-05-282780","article-title":"Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma","volume":"116","author":"Green","year":"2010","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1158\/1078-0432.CCR-11-1942","article-title":"Constitutive AP-1 Activity and EBV Infection Induce PD-L1 in Hodgkin Lymphomas and Posttransplant Lymphoproliferative Disorders: Implications for Targeted Therapy","volume":"18","author":"Green","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1200\/JCO.2016.66.4482","article-title":"PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome","volume":"34","author":"Roemer","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Ma, S.-D., Xu, X., Jones, R., Delecluse, H.-J., Zumwalde, N.A., Sharma, A., Gumperz, J.E., and Kenney, S.C. (2016). PD-1\/CTLA-4 Blockade Inhibits Epstein-Barr Virus-Induced Lymphoma Growth in a Cord Blood Humanized-Mouse Model. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005642"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1038\/s41375-019-0380-5","article-title":"Frequent Structural Variations Involving Programmed Death Ligands in Epstein-Barr Virus-Associated Lymphomas","volume":"33","author":"Kataoka","year":"2019","journal-title":"Leukemia"},{"key":"ref_54","first-page":"4134","article-title":"PD-L1 Is up-Regulated By EBV-Driven LMP1 through NF-\u03bab Pathway and Correlates with Poor Prognosis in Natural Killer\/T-Cell Lymphoma","volume":"128","author":"Bi","year":"2016","journal-title":"J. Hematol. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"12189","DOI":"10.18632\/oncotarget.2608","article-title":"EBV-driven LMP1 and IFN-\u03b3 up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy","volume":"5","author":"Fang","year":"2014","journal-title":"Oncotarget"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1002\/ijc.23374","article-title":"Authentication of nasopharyngeal carcinoma tumor lines","volume":"122","author":"Chan","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4268","DOI":"10.1096\/fj.14-266718","article-title":"Genetic profiling reveals an alarming rate of cross-contamination among human cell lines used in China","volume":"29","author":"Ye","year":"2015","journal-title":"FASEB J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.canlet.2016.07.031","article-title":"\u201cCell Identity\u201d Crisis: Another Call for Immediate Action","volume":"381","author":"Marques","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/s41375-018-0178-x","article-title":"Epstein\u2212Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas","volume":"33","author":"Anastasiadou","year":"2018","journal-title":"Leukemia"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1182\/blood.2019000889","article-title":"EBV MicroRNA-BHRF1-2-5p Targets the 3\u2019UTR of Immune Checkpoint Ligands PD-L1 and PD-L2","volume":"134","author":"Cristino","year":"2019","journal-title":"Blood"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1038\/s41467-022-28479-2","article-title":"EBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1007\/s10120-020-01059-3","article-title":"Epstein-Barr Virus-Encoded MiR-BART5-5p Upregulates PD-L1 through PIAS3\/PSTAT3 Modulation, Worsening Clinical Outcomes of PD-L1-Positive Gastric Carcinomas","volume":"23","author":"Yoon","year":"2020","journal-title":"Gastric Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6010","DOI":"10.1158\/0008-5472.CAN-19-0615","article-title":"Integrated Pan-Cancer Map of EBV-Associated Neoplasms Reveals Functional Host\u2013Virus Interactions","volume":"79","author":"Chakravorty","year":"2019","journal-title":"Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13027-019-0234-9","article-title":"B7-H4 Is Highly Expressed in Aggressive Epstein-Barr Virus Positive Diffuse Large B-Cell Lymphoma and Inhibits Apoptosis through Upregulating Erk1\/2 and Akt Signalling Pathways","volume":"14","author":"Jiang","year":"2019","journal-title":"Infect. Agent Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e1293215","DOI":"10.1080\/2162402X.2017.1293215","article-title":"The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1\/PD-1: A future perspective for a combined gastric cancer therapy?","volume":"6","author":"Behrens","year":"2017","journal-title":"OncoImmunology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"176","DOI":"10.18632\/genesandcancer.180","article-title":"The promising immune checkpoint LAG-3: From tumor microenvironment to cancer immunotherapy","volume":"9","author":"Long","year":"2018","journal-title":"Genes Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e000911","DOI":"10.1136\/jitc-2020-000911","article-title":"Tim-3 finds its place in the cancer immunotherapy landscape","volume":"8","author":"Acharya","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/cmi.2017.148","article-title":"The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation","volume":"15","author":"Xu","year":"2018","journal-title":"Cell. Mol. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1182\/blood-2017-07-740993","article-title":"PD-1 expression and clinical PD-1 blockade in B-cell lymphomas","volume":"131","author":"Zhou","year":"2018","journal-title":"Blood"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1182\/blood-2015-02-629600","article-title":"Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma","volume":"126","author":"Kiyasu","year":"2015","journal-title":"Blood"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/leu.2016.385","article-title":"Soluble programmed death-ligand 1 as a prognostic biomarker for overall survival in patients with diffuse large B-cell lymphoma: A replication study and combined analysis of 508 patients","volume":"31","author":"Rossille","year":"2017","journal-title":"Leukemia"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"290","DOI":"10.20892\/j.issn.2095-3941.2018.0047","article-title":"The Prognostic Value of Programmed Cell Death Ligand 1 Expression in Non-Hodgkin Lymphoma: A Meta-Analysis","volume":"15","author":"Zhao","year":"2018","journal-title":"Cancer Biol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1182\/bloodadvances.2019001390","article-title":"LAG3: A novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma","volume":"4","author":"Keane","year":"2020","journal-title":"Blood Adv."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13000-020-00979-z","article-title":"Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas","volume":"15","author":"Choi","year":"2020","journal-title":"Diagn. Pathol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Nakayama, A., Abe, H., Kunita, A., Saito, R., Kanda, T., Yamashita, H., Seto, Y., Ishikawa, S., and Fukayama, M. (2019). Viral loads correlate with upregulation of PD-L1 and worse patient prognosis in Epstein-Barr Virus-associated gastric carcinoma. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211358"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1208\/s12248-021-00574-0","article-title":"Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics","volume":"23","author":"Twomey","year":"2021","journal-title":"AAPS J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s41577-020-0306-5","article-title":"A guide to cancer immunotherapy: From T cell basic science to clinical practice","volume":"20","author":"Waldman","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa1411087","article-title":"PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin\u2019s Lymphoma","volume":"372","author":"Ansell","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/S1470-2045(16)30167-X","article-title":"Nivolumab for Classical Hodgkin\u2019s Lymphoma after Failure of Both Autologous Stem-Cell Transplantation and Brentuximab Vedotin: A Multicentre, Multicohort, Single-Arm Phase 2 Trial","volume":"17","author":"Younes","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1200\/JCO.2016.72.1316","article-title":"Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed\/Refractory Classic Hodgkin Lymphoma","volume":"35","author":"Chen","year":"2017","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3389\/fphar.2017.00049","article-title":"Current Diagnosis and Management of Immune Related Adverse Events (IrAEs) Induced by Immune Checkpoint Inhibitor Therapy","volume":"8","author":"Kumar","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cell.2017.01.017","article-title":"Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy","volume":"168","author":"Sharma","year":"2017","journal-title":"Cell"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.trecan.2020.02.022","article-title":"Turning Cold into Hot: Firing up the Tumor Microenvironment","volume":"6","author":"Duan","year":"2020","journal-title":"Trends Cancer"},{"key":"ref_84","first-page":"2059","article-title":"The microenvironmental niche in classic Hodgkin lymphoma is enriched for CTLA-4-positive T cells that are PD-1-negative","volume":"134","author":"Patel","year":"2019","journal-title":"Blood"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3462","DOI":"10.1158\/1078-0432.CCR-13-0855","article-title":"PD-L1 Expression Is Characteristic of a Subset of Aggressive B-cell Lymphomas and Virus-Associated Malignancies","volume":"19","author":"Chen","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.humpath.2017.10.029","article-title":"Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes","volume":"71","author":"Panjwani","year":"2018","journal-title":"Hum. Pathol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrc3774","article-title":"The tumour microenvironment in B cell lymphomas","volume":"14","author":"Scott","year":"2014","journal-title":"Nat. Cancer"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"5316","DOI":"10.1182\/blood-2018-99-110732","article-title":"Programmed Death-1 and Programmed Death-Ligand 1 Expression Patterns in Pediatric Lymphoma","volume":"132","author":"Tamura","year":"2018","journal-title":"Blood"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1182\/blood.2019004126","article-title":"Epigenetic reprogramming sensitizes immunologically silent EBV+ lymphomas to virus-directed immunotherapy","volume":"135","author":"Dalton","year":"2020","journal-title":"Blood"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.ccr.2011.11.006","article-title":"Combined Genetic Inactivation of \u03b22-Microglobulin and CD58 Reveals Frequent Escape from Immune Recognition in Diffuse Large B Cell Lymphoma","volume":"20","author":"Lieu","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/nature23465","article-title":"CDK4\/6 Inhibition Triggers Anti-Tumour Immunity","volume":"548","author":"Goel","year":"2017","journal-title":"Nature"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1158\/2159-8290.CD-17-0915","article-title":"CDK4\/6 Inhibition Augments Antitumor Immunity by Enhancing T-Cell Activation","volume":"8","author":"Deng","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1111\/j.1365-2567.2009.03111.x","article-title":"Cell cycle arrest induced by engagement of B7-H4 on Epstein-Barr virus-positive B-cell lymphoma cell lines","volume":"128","author":"Song","year":"2009","journal-title":"Immunology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1038\/s41591-018-0101-z","article-title":"Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer","volume":"24","author":"Kim","year":"2018","journal-title":"Nat. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"611","DOI":"10.4143\/crt.2018.191","article-title":"Comparison of Efficacy of Pembrolizumab between Epstein-Barr Virus\u2012Positive and \u2012Negative Relapsed or Refractory Non-Hodgkin Lymphomas","volume":"51","author":"Kim","year":"2019","journal-title":"Cancer Res. Treat."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"8595","DOI":"10.2147\/OTT.S219512","article-title":"Primary Pulmonary Lymphoepithelioma-Like Carcinoma Response Favorably to Nivolumab: A Case Report","volume":"12","author":"Qiu","year":"2019","journal-title":"OncoTargets Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e238","DOI":"10.1016\/j.cllc.2018.12.015","article-title":"EBV-positive Primary Pulmonary Lymphoepithelioma-like Carcinoma Response to PD-L1 Blockade","volume":"20","author":"Narayanan","year":"2019","journal-title":"Clin. Lung Cancer"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/3\/397\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:31:53Z","timestamp":1760135513000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/3\/397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,4]]},"references-count":97,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["biom12030397"],"URL":"https:\/\/doi.org\/10.3390\/biom12030397","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,4]]}}}