Induction of EBV–Latent Membrane Protein 1–Specific MHC Class II–Restricted T-Cell Responses against Natural Killer Lymphoma Cells

Kobayashi, Hiroya; Nagato, Toshihiro; Takahara, Miki; Sato, Keisuke; Kimura, Shoji; Aoki, Naoko; Azumi, Makoto; Tateno, Masatoshi; Harabuchi, Yasuaki; Celis, Esteban

doi:10.1158/0008-5472.can-07-3212

Cited by 38 publications

(29 citation statements)

References 49 publications

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“…Our results showed that these malignant T and NK cells had the machinery for antigen-processing and presentation, were recognized by polyclonal effectors containing LMP2-specific CTLs as minor populations, and more importantly, by LMP2-specific CD8 ϩ clones; efficiently recognizing multiple LMP2 epitopes across 3 different restriction elements. These data greatly strengthen the isolated reports describing killing of T and NK lines by EBNA1 41 or LMP1 42,43 clones by extending to the most immunogenic and clinically relevant of available targets, LMP2. Our data provide a rationale to pursue adoptive CTL immunotherapy for patients with ENKTL and CAEBV.…”

Section: Discussionsupporting

confidence: 82%

A novel latent membrane 2 transcript expressed in Epstein-Barr virus–positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy

Fox

Haigh

Taylor

et al. 2010

Blood

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IntroductionExpression of viral proteins in Epstein-Barr virus (EBV)-associated tumors has allowed specific therapeutic targeting of such antigens with cellular immunotherapies. This is best exemplified by the highly immunogenic lymphoproliferations arising in the T cell-compromised host after allogeneic organ or hematopoietic stem cell transplantation (posttransplant lymphoproliferative disease; PTLD), 1 which express the full complement of EBV latent antigens as seen in lymphoblastoid cell lines (LCLs) generated by EBV infection of B lymphocytes in vitro. 2 A more restricted pattern of EBV latent gene expression is manifest in malignancies such as Hodgkin lymphoma (HL). The so-called Latency II characteristic of these tumors confines expression of EBV-encoded proteins to Epstein-Barr virus nuclear antigen 1 (EBNA1), latent membrane protein 1 (LMP1), LMP2A, and LMP2B. This has presented a greater challenge for clinicians hoping to target such tumors with antigen-specific adoptive T-cell therapy, because these Latency II viral proteins are significantly less immunogenic than the additional Latency III viral antigens, particularly EBNA3A, EBNA3B, and EBNA3C, expressed in PTLD. 2 Cytotoxic T-cell lines (CTLs) generated by in vitro stimulation with LCLs contain low frequencies of T cells specific for LMP2, LMP1, and EBNA1, with accordingly suboptimal clinical efficacy against HL. 3 To address this, investigators have recently focused on skewing the EBVspecific CTL response by an in vitro system of LMP2 overexpression in antigen-presenting cells resulting in an expansion of polyclonal populations of both CD4 ϩ and CD8 ϩ effectors specific for LMP2. 4 This approach has achieved sustained tumor responses (including some complete responses) in patients with relapsed/ refractory HL, with evidence of in vivo expansion and penetration to tumor sites of LMP2-specific T cells. 5 EBV-associated malignancies of natural killer (NK) and T-cell origin are also thought to display a 'Latency II' pattern of EBV gene expression. Extra-nodal NK/T-cell lymphoma (ENKTL) is an aggressive malignancy, occurring at a median age of 50 years and most commonly presenting in the upper-aerodigestive tract. 6 EBV is invariably present within the malignant cells in all cases of ENKTL, irrespective of geographical origin. 7 The clonal and episomal form of EBV in tumor biopsy material 8 implicates a pathogenic role for the virus in the early stages of lymphomagenesis. Although most reports suggest that EBV antigen expression in ENKTL is of a Latency II type, it should be noted that, when expressed, LMP1 protein is usually evident in a subpopulation of malignant cells, while detection of LMP2 in tumor tissue has only been shown at the mRNA level. 9 Also recognized within the Submitted June 23, 2010; accepted July 22, 2010. Prepublished online as Blood First Edition paper, July 29, 2010; DOI 10.1182 DOI 10. /blood-2010 An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supple...

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Section: Discussionsupporting

confidence: 82%

A novel latent membrane 2 transcript expressed in Epstein-Barr virus–positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy

Fox

Haigh

Taylor

et al. 2010

Blood

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“…The attention has been focused on cytotoxic CD4 + T cells, which proved to be effective, at least in vitro, not only against EBV LCL but also, more importantly, against infected NK or T cells, the natural target in NK/Tcell lymphoma and CAEBV. 86,87 Such observations differ from the previous reports related to these diseases [82][83][84][85] which only demonstrated the activity against LCL that express a larger pattern of viral antigen and costimulatory molecules than EBV-infected NK/T cells.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Ncontrasting

confidence: 85%

The interplay between Epstein-Barr virus and the immune system: a rationale for adoptive cell therapy of EBV-related disorders

Merlo¹,

Turrini²,

Dolcetti³

et al. 2010

Haematologica

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The Epstein-Barr virus has evolved a plethora of strategies to evade immune system recognition and to establish latent infection in memory B cells, where the virus resides lifelong without any consequence in the majority of individuals. However, some imbalances in the equilibrium between the inherent virus transforming properties and the host immune system can lead to the development of different tumors, such as lymphoproliferative disorders, Hodgkin's lymphoma, Burkitt's lymphoma, and nasopharyngeal carcinoma. The expression of viral antigens in malignant cells makes them suitable targets for immunotherapeutic approaches, which are mainly based on the ex vivo expansion of EBV-specific T cells. Indeed, the infusion of virus-specific cytotoxic T lymphocytes has proved not only to be safe and effective, but also capable of restoring or inducing a protective anti-virus immunity, which is lacking, albeit to a different extent, in every EBV-driven malignancy. The purpose of this review is to summarize the results of adoptive immunotherapy approaches for EBV-related malignancies, with particular emphasis on the immunological and virological aspects linked to the clinical responses obtained. Data collected confirm the clinical relevance of the use of EBV-specific cytotoxic T lymphocytes in the field of adoptive immunotherapy and suggest the increasing importance of this approach also against other tumors, concurrent with the increasing knowledge of the intimate and continuous interplay between the virus and the host immune system. -related disorders. Haematologica 210;95(10):1769-1777. doi:10.3324/haematol.2010 Citation: Merlo A, Turrini R, Dolcetti R, Martorelli D, Muraro E, Comoli P, and Rosato A. The interplay between Epstein-Barr virus and the immune system: a rationale for adoptive cell therapy of EBV ©2010 Ferrata Storti Foundation. This is an open-access paper.The interplay between Epstein-Barr virus and the immune system: a rationale for adoptive cell therapy of EBV-related disorders

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“…Although LMP1 may render the cell malignant phenotype, these alterations should be involved in host immune response and may affect the manner of tumor progression. Previous in vitro studies show that cytotoxic T cells against LMP1 can directly kill ENKLderived cell lines (35,36). Therefore, LMP1 may have reciprocal effects on the expressing cells, that is, even though LMP1-expressing cells show a malignant phenotype, an extrinsic immune system can eradicate these cells in vivo.…”

Section: Discussionmentioning

confidence: 99%

Expression of Epstein-Barr Virus–Encoded Proteins in Extranodal NK/T-cell Lymphoma, Nasal Type (ENKL): Differences in Biologic and Clinical Behaviors of LMP1-Positive and -Negative ENKL

Kanemitsu

Isobe

Masuda

et al. 2012

Clinical Cancer Research

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Purpose: Extranodal NK/T-cell lymphoma, nasal type (ENKL) is closely associated with Epstein-Barr virus (EBV). To elucidate its pathogenetic role, we examined the expression profiles of EBV-encoded proteins, especially focusing on latent membrane protein 1 (LMP1).Experimental Design: Immunohistochemistry was carried out using clinical samples from ENKL cases, which were diagnosed between 1996 and 2010 at our institution. We statistically assessed the correlation between LMP1 positivity and the clinicopathologic data and further examined phosphorylation status of NF-kB RelA and Akt in ENKL cell lines.Results: Most of the 30 examined cases showed pleomorphic morphology, natural killer cell immunophenotype, and a localized disease. Immunohistochemistry detected EBERs, but not EBNA2, in all cases. LMP1 and LMP2A were positive in 22 (73.3%) and 12 cases (40.0%), respectively. LMP1-positive cases tended to show a localized disease (P ¼ 0.060, the Fisher exact test). Nuclear localization of phosphorylated RelA and detection of phosphorylated Akt were predominantly observed in LMP1-positive cases (P ¼ 0.002 and P < 0.001, respectively, the Fisher exact test). RNA silencing experiments of LMP1 in Hank1 cells suggested a positive correlation between LMP1 expression and phosphorylation of RelA and Akt. With a median follow-up period of 26.7 months (range, 0.2-142.3 months), the 2.5-year overall survival rates for LMP1-positive and -negative cases were estimated at 78.3% and 12.5%, respectively (P ¼ 0.001, log-rank test).Conclusions: LMP1 expression shows correlations with phosphorylation of RelA and Akt and possibly has a favorable impact on clinical outcome in ENKL.

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Induction of EBV–Latent Membrane Protein 1–Specific MHC Class II–Restricted T-Cell Responses against Natural Killer Lymphoma Cells

Cited by 38 publications

References 49 publications

A novel latent membrane 2 transcript expressed in Epstein-Barr virus–positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy

A novel latent membrane 2 transcript expressed in Epstein-Barr virus–positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy

The interplay between Epstein-Barr virus and the immune system: a rationale for adoptive cell therapy of EBV-related disorders

Expression of Epstein-Barr Virus–Encoded Proteins in Extranodal NK/T-cell Lymphoma, Nasal Type (ENKL): Differences in Biologic and Clinical Behaviors of LMP1-Positive and -Negative ENKL

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