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Characterization of the humoral immune response to the EBV proteome in extranodal NK/T-cell lymphoma.

ABSTRACT: Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma samples from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case-control study. The EBV-directed serological response was characterized using a protein microarray that measured IgG and IgA antibodies against 202 protein sequences representing the entire EBV proteome. We analyzed 157 IgG antibodies and 127 IgA antibodies that fulfilled quality control requirements. Associations between EBV serology and NKTCL status were disproportionately observed for IgG rather than IgA antibodies. Nine anti-EBV IgG responses were significantly elevated in NKTCL cases compared with controls and had ORs_{highest vs. lowest tertile} > 6.0 (Bonferroni-corrected P-values < 0.05). Among these nine elevated IgG responses in NKTCL patients, three IgG antibodies (all targeting EBNA3A) are novel and have not been observed for other EBV-associated tumors of B-cell or epithelial origin. IgG antibodies against EBNA1, which have consistently been elevated in other EBV-associated tumors, were not elevated in NKTCL cases. We characterize the antibody response against EBV for patients with NKTCL and identify IgG antibody responses against six distinct EBV proteins. Our findings suggest distinct serologic patterns of this NK/T-cell lymphoma compared with other EBV-associated tumors of B-cell or epithelial origin.

SUBMITTER: Liu Z

PROVIDER: S-EPMC8655014 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Characterization of the humoral immune response to the EBV proteome in extranodal NK/T-cell lymphoma.

Liu Zhiwei Z Sarathkumara Yomani D YD Chan John K C JKC Kwong Yok-Lam YL Lam Tai Hing TH Ip Dennis Kai Ming DKM Chiu Brian C-H BC Xu Jun J Su Yu-Chieh YC Proietti Carla C Cooper Martha M MM Yu Kelly J KJ Bassig Bryan B Liang Raymond R Hu Wei W Ji Bu-Tian BT Coghill Anna E AE Pfeiffer Ruth M RM Hildesheim Allan A Rothman Nathaniel N Doolan Denise L DL Lan Qing Q

Scientific reports 20211208 1

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma samples from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case-control ...[more]

PMID: 34880297

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Project description:Extranodal natural killer/T cell lymphoma-nasal type (EN-NK/T-NT) is extremely rare in Western countries; however, it is the most common subtype of peripheral T cell lymphoma in China. Despite this, there are a limited number of clinicopathological research studies on Epstein-Barr virus (EBV)-negative EN-NK/T-NTs. EBV-negative EN-NK/T-NT is a rare disease type, which has not been fully investigated. If other diagnostic criteria are met, such as the lesions being located predominantly in the upper aerodigestive tract, the presence of angiocentricity or angioinvasion, necrosis and expression of NK/T-cell phenotype, EN-NK/T-NT may be diagnosed, even if EBV is negative. In the present study, 99 cases of EN-NK/T-NTs were analyzed retrospectively, among which seven cases were EBV-negative EN-NK/T-NTs and selected for further investigation. In addition, the present study reviewed previously published research into EN-NK/T-NT, highlighting that EBV-negative EN-NK/T-NT is rare and that its geographical distribution is mainly in countries in Asia, Central America and South America. Patients with EBV-negative EN-NK/T-NT were all of Chinese ethnicity, with a median age of 32 years and primarily female. Furthermore, these patients shared similar clinicopathological characteristics (such as the tumor occurring mainly in the upper aerodigestive tract, the presence of vascular destruction, necrosis and cytotoxic phenotypes) to patients with EBV-positive EN-NK/T-NT. Immunohistochemistry and molecular analysis results indicated that tumor cells were primarily of NK or cytotoxic T origin; however, EBV-encoded small RNAs were not detected in any of these cases. Among the immunochemistry markers, T-bet was statistical significantly different between EBV-positive and -negative cases. Fluorescence in situ hybridization was also performed in two EBV-negative cases, including one case with a co-deletion of 6q21 and PR/SET domain 1 genes. There was only available follow-up data in 3/5 patients who survived for 37-113 months (median, 40 months). As EN-NK/T-NT can be diagnosed, even when EBV is negative, awareness of this subtype may prevent misdiagnosis or delayed diagnosis.

Project description:Extranodal NK/T cell lymphoma, nasal type (ENKTL) is an aggressive malignancy with a dismal prognosis. Although L-asparaginase-based chemotherapy has resulted in improved response rates, relapse occurs in up to 50% of patients with disseminated disease. There is hence an urgent need for effective targeted therapy, especially for patients with relapsed or refractory disease. Novel insights gleaned from high-throughput molecular and genomic profiling studies in recent years have contributed significantly to the understanding of the molecular biology of ENKTL, which exemplifies many of the hallmarks of cancer. Deregulated pro-proliferative signaling pathways, such as the Janus-associated kinase/signal transducer and activator of transcription (JAK/STAT), platelet-derived growth factor (PDGF), Aurora kinase, MYC, and NF-κB, have been identified as potential therapeutic targets. The discovery of the non-canonical function of EZH2 as a pro-proliferative transcriptional co-activator has shed further light on the pathogenesis of ENKTL. Loss of key tumor suppressor genes located on chromosome 6q21 also plays an important role. The best-studied examples include PR domain zinc finger protein 1(PRDM1), protein tyrosine phosphatase kappa (PTPRK), and FOXO3. Promoter hypermethylation has been shown to result in the downregulation of other tumor suppressor genes in ENKTL, which may be potentially targeted through hypomethylating agents. Deregulation of apoptosis through p53 mutations and upregulation of the anti-apoptotic protein, survivin, may provide a further growth advantage to this tumor. A deranged DNA damage response as a result of the aberration of ataxia telangiectasia-related (ATR) kinases can lead to significant genomic instability and may contribute to chemoresistance of ENKTL. Recently, immune evasion has emerged as a critical pathway for survival in ENKTL and may be a consequence of HLA dysregulation or STAT3-driven upregulation of programmed cell death ligand 1 (PD-L1). Immunotherapy via inhibition of programmed cell death 1 (PD-1)/PD-L1 checkpoint signaling holds great promise as a novel therapeutic option. In this review, we present an overview of the key molecular and pathogenic pathways in ENKTL, organized using the framework of the "hallmarks of cancer" as described by Hanahan and Weinberg, with a focus on those with the greatest translational potential.

Project description:Extranodal NK/T-cell lymphoma (ENKTCL) is a highly aggressive mature NK/T-cell neoplasm marked by NK-cell phenotypic expression of CD3ε and CD56. While the disease is reported worldwide, there is a significant geographic variation with its highest incidence in East Asian countries possibly related to the frequent early childhood exposure of Epstein-Barr virus (EBV) and specific ethnic-genetical background, which contributes to the tumorigenesis. Historically, anthracycline-based chemotherapy such as CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) was used, but resulted in poor outcomes. This is due in part to intrinsic ENKTCL resistance to anthracycline caused by high expression levels of P-glycoprotein. The recent application of combined modality therapy with concurrent or sequential radiation therapy for early stage disease, along with non-anthracycline-based chemotherapy regimens consisting of drugs independent of P-glycoprotein have significantly improved clinical outcomes. Particularly, this neoplasm shows high sensitivity to l-asparaginase as NK-cells lack asparagine synthase activity. Even still, outcomes of patients with advanced stage disease or those with relapsed/recurrent disease are dismal with overall survival of generally a few months. Thus, novel therapies are needed for this population. Clinical activity of targeted antibodies along with antibody-drug conjugates, such as daratumumab (naked anti-CD38 antibody) and brentuximab vedotin (anti-CD30 antibody conjugated with auristatin E), have been reported. Further promising data have been shown with checkpoint inhibitors as high levels of programmed death-ligand 1 expression are observed in ENKTCL due to EBV-driven overexpression of the latent membrane proteins [latent membrane protein 1 (LMP1) and LMP2] with activation of the NF-κB/MAPK pathways. Initial case series with programmed death 1 inhibitors showed an overall response rate of 100% in seven relapsed patients including five with a complete response (CR). Furthermore, cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 have shown encouraging results with durable CRs as either maintenance therapy after initial induction chemotherapy or in the relapsed/refractory setting. In this paper, we review this exciting field of novel immunotherapy options against ENKTCL that hopefully will change the treatment paradigm in this deadly disease.

Project description:Extranodal NK/T-cell lymphoma (ENKTCL) is the most common subtype of T/NK-cell lymphoma in Asia and Latin America, but very rare in North American and Europe. Patient survival has improved significantly over the past two decades. However, standard treatment has not yet been established, although dozens of prospective trials have been conducted. To help understand how the treatment of ENKTCL has evolved in the past and what trends lie ahead, we have comprehensively reviewed the treatment of this aggressive malignancy, with a particular focus on neglected or unanswered issues, such as the optimal staging method, the best partner of asparaginase (Asp), the individualized administration of Asp, the preferred sequence of CT and RT and so on. Overall, the 5-year overall survival (OS) of patients with Ann Arbor stage I/II disease increased from < 50% in the early 20th century to > 80% in recent years, and the median OS of patients with Ann Arbor stage III/IV disease increased from < 1 year to more than 3 years. The improvement in patient survival is largely attributable to advances in radiation technology and the introduction of Asp and anti-PD-1/PD-L1 immunotherapy into practice. Radiotherapy is essential for patients with early-stage disease, while Asp-based chemotherapy (CT) and PD-1/PD-L1 inhibitors significantly improved the prognosis of patients with advanced-stage disease. ENKTCL management is trending toward simpler regimens, less toxicity, and higher efficacy. Novel drugs, such as manufactured T cells, monoclonal antibodies, and small molecule inhibitors, are being intensively investigated. Based on the fact that ENKTCL is highly resistant to cytotoxic drugs except Asp, and aggressive CT leads to higher toxicity rather than better outcomes, we recommend it is unnecessary to expend additional resources to compare different combinations of Asp with cytotoxic agents. Instead, more efforts should be made to optimize the use of Asp and immunotherapy to maximize efficacy and minimize toxicity, explore ways to overcome resistance to Asp and immunotherapy, identify novel treatment targets, and define subpopulations who may benefit more from specific treatments.

Dataset Information

Characterization of the humoral immune response to the EBV proteome in extranodal NK/T-cell lymphoma.

Publications

Characterization of the humoral immune response to the EBV proteome in extranodal NK/T-cell lymphoma.

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