Heterogeneity of HLA and EBER expression in epstein-barr virus-associated nasopharyngeal carcinoma

Yao, Yunhong; Minter, Helena A.; Chen, Xiaoyi; Reynolds, Gary; Bromley, Michael; Arrand, John R.

doi:10.1002/1097-0215(20001215)88:6<949::aid-ijc18>3.0.co;2-6

Cited by 48 publications

(21 citation statements)

References 31 publications

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“…Apart from the interference with cell death signalling pathways mentioned above, the failure of CTLs to induce tumour cell lysis may be the result of several other mechanisms. Interference with the antigen presentation pathway by neoplastic cells may be one of these, since down‐regulation of MHC class I proteins was observed in a significant minority of cases, in agreement with a recent paper by Yao et al 31.…”

Section: Discussionsupporting

confidence: 90%

High numbers of granzyme B/CD8‐positive tumour‐infiltrating lymphocytes in nasopharyngeal carcinoma biopsies predict rapid fatal outcome in patients treated with curative intent

Oudejans

Harijadi

Kummer

et al. 2002

The Journal of Pathology

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This study determined whether tumour-infiltrating lymphocytes (TILs) in nasopharyngeal carcinomas (NPCs) include activated cytotoxic T lymphocytes (CTLs) and whether the numbers of activated CTLs in these biopsies are related to clinical outcome. Moreover, the study investigated whether the numbers of activated CTLs are associated with the expression of MHC class I proteins and the granzyme B antagonist PI-9 in the tumour cells. Forty-three Indonesian NPC patients (T(1-3), N(1-3), M(0)), who were treated with curative intent by radiotherapy only, were studied. Tumour-infiltrating activated CTLs were detected using antibodies against granzyme B, CD8, and CD56. Expression of MHC class I proteins and PI-9 was also determined by immunohistochemistry. Granzyme B-positive TILs were detected in all NPC biopsies. The presence of a high percentage (>25%) of granzyme B-positive TILs appeared to be a very strong predictor of a rapid fatal clinical outcome, independent of stage. Complete absence of MHC class I heavy chain expression in tumour cells was observed in 11 of 31 evaluable cases and low levels were observed in seven additional cases. No association between MHC class I expression and the numbers of granzyme B-positive TILs was observed. Expression of the granzyme B antagonist PI-9 in tumour cells was detected in three cases. It is concluded that the presence of many granzyme B-positive TILs in a selected group of Indonesian NPC patients is a strong and stage-independent marker for a rapid fatal clinical outcome.

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Section: Discussionsupporting

confidence: 90%

High numbers of granzyme B/CD8‐positive tumour‐infiltrating lymphocytes in nasopharyngeal carcinoma biopsies predict rapid fatal outcome in patients treated with curative intent

Oudejans

Harijadi

Kummer

et al. 2002

The Journal of Pathology

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“…Immunoblotting for TFIIIC subunits was performed as described previously [29]. Immunohistochemical staining and EBER in situ hybridisation were performed on biopsies used in previous studies [59] and were conducted as described therein. For immunohistochemistry, antibody 3238 to TFIIIC-102 [29] was used at a dilution of 1:100 following standard techniques.…”

Section: Methodsmentioning

confidence: 99%

Epstein-Barr virus-encoded EBNA1 enhances RNA polymerase III-dependent EBER expression through induction of EBER-associated cellular transcription factors

et al. 2010

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BackgroundEpstein-Barr Virus (EBV)-encoded RNAs (EBERs) are non-polyadenylated RNA molecules transcribed from the EBV genome by RNA polymerase III (pol III). EBERs are the most abundant viral latent gene products, although the precise mechanisms by which EBV is able to achieve such high levels of EBER expression are not fully understood. Previously EBV has been demonstrated to induce transcription factors associated with EBER expression, including pol III transcription factors and ATF-2. We have recently demonstrated that EBV-encoded nuclear antigen-1 (EBNA1) induces cellular transcription factors, and given these findings, we investigated the role of EBNA1 in induction of EBER-associated transcription factors.ResultsOur data confirm that in epithelial cells EBNA1 can enhance cellular pol III transcription. Transient expression of EBNA1 in Ad/AH cells stably expressing the EBERs led to induction of both EBER1 and EBER2 and conversely, expression of a dominant negative EBNA1 led to reduced EBER expression in EBV-infected Ad/AH cells. EBNA1 can induce transcription factors used by EBER genes, including TFIIIC, ATF-2 and c-Myc. A variant chromatin precipitation procedure showed that EBNA1 is associated with the promoters of these genes but not with the promoters of pol III-transcribed genes, including the EBERs themselves. Using shRNA knock-down, we confirm the significance of both ATF-2 and c-Myc in EBER expression. Further, functional induction of a c-Myc fusion protein led to increased EBER expression, providing c-Myc binding sites upstream of EBER1 were intact. In vivo studies confirm elevated levels of the 102 kD subunit of TFIIIC in the tumour cells of EBV-positive nasopharyngeal carcinoma biopsies.ConclusionsOur findings reveal that EBNA1 is able to enhance EBER expression through induction of cellular transcription factors and add to the repertoire of EBNA1's transcription-regulatory properties.

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“…However, it requires the tumor cells to express MHC class I and be low in apoptosis resistance function that might counteract the granzyme-B attack by CTLs. Previous studies have indicated significant MHC class I heterogeneity among NPC cases as well as expression of Bcl-2 and XIAP, which correlated with poor prognosis 122–124,183–185. In addition, the immunosuppressive microenvironment of NPC cells in vivo may silence infiltrating activated T-cells, thereby diminishing the intended therapeutic effect 121,122.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Therapeutic implications of Epstein–Barr virus infection for the treatment of nasopharyngeal carcinoma

Hutajulu¹,

Kurnianda²,

Tan³

et al. 2014

TCRM

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Nasopharyngeal carcinoma (NPC) is highly endemic in certain regions including the People’s Republic of China and Southeast Asia. Its etiology is unique and multifactorial, involving genetic background, epigenetic, and environment factors, including Epstein–Barr virus (EBV) infection. The presence of EBV in all tumor cells, aberrant pattern of antibodies against EBV antigens in patient sera, and elevated viral DNA in patient circulation as well as nasopharyngeal site underline the role of EBV during NPC development. In NPC tumors, EBV expresses latency type II, where three EBV-encoded proteins, Epstein–Barr nuclear antigen 1, latent membrane protein 1 and 2 (LMP1, 2), are expressed along with BamH1-A rightward reading frame 1, Epstein–Barr virus-encoded small nuclear RNAs, and BamH1-A rightward transcripts. Among all encoded proteins, LMP1 plays a central role in the propagation of NPC. Standard treatment of NPC consists of radiotherapy with or without chemotherapy for early stage, concurrent chemoradiotherapy in locally advanced tumors, and palliative systemic chemotherapy in metastatic disease. However, this standard care has limitations, allowing recurrences and disease progression in a certain proportion of cases. Although the pathophysiological link and molecular process of EBV-induced oncogenesis are not fully understood, therapeutic approaches targeting the virus may increase the cure rate and add clinical benefit. The promising results of early phase clinical trials on EBV-specific immunotherapy, epigenetic therapy, and treatment with viral lytic induction offer new options for treating NPC.

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Heterogeneity of HLA and EBER expression in epstein-barr virus-associated nasopharyngeal carcinoma

Cited by 48 publications

References 31 publications

High numbers of granzyme B/CD8‐positive tumour‐infiltrating lymphocytes in nasopharyngeal carcinoma biopsies predict rapid fatal outcome in patients treated with curative intent

High numbers of granzyme B/CD8‐positive tumour‐infiltrating lymphocytes in nasopharyngeal carcinoma biopsies predict rapid fatal outcome in patients treated with curative intent

Epstein-Barr virus-encoded EBNA1 enhances RNA polymerase III-dependent EBER expression through induction of EBER-associated cellular transcription factors

Therapeutic implications of Epstein–Barr virus infection for the treatment of nasopharyngeal carcinoma

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Heterogeneity of HLA and EBER expression in epstein-barr virus-associated nasopharyngeal carcinoma

Cited by 48 publications

References 31 publications

High numbers of granzyme B/CD8‐positive tumour‐infiltrating lymphocytes in nasopharyngeal carcinoma biopsies predict rapid fatal outcome in patients treated with curative intent

High numbers of granzyme B/CD8‐positive tumour‐infiltrating lymphocytes in nasopharyngeal carcinoma biopsies predict rapid fatal outcome in patients treated with curative intent

Epstein-Barr virus-encoded EBNA1 enhances RNA polymerase III-dependent EBER expression through induction of EBER-associated cellular transcription factors

Therapeutic implications of Epstein&ndash;Barr virus infection for the treatment of nasopharyngeal carcinoma

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Therapeutic implications of Epstein–Barr virus infection for the treatment of nasopharyngeal carcinoma