scholarly journals Intratumoral CXCR5+CD8+T associates with favorable clinical outcomes and immunogenic contexture in gastric cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jieti Wang ◽  
Ruochen Li ◽  
Yifan Cao ◽  
Yun Gu ◽  
Hanji Fang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
T Cells ◽  
Epstein Barr Virus ◽  
Effector Memory ◽  
Feature Identification ◽  
Barr Virus ◽  
T Cell Infiltration ◽  
Epstein Barr ◽  
Gastric Cancer Patients

AbstractStudies that examined an association between CD8+T and prognosis in gastric cancer are inconsistent, and a distinct population of CXCR5+CD8+T associated with better overall survival has been reported among various malignancies. Here, we show that the abundance of intratumoral CXCR5+CD8+T cells is associated with better overall survival in patients with gastric cancer. Patients with TNM II + III gastric cancer with higher intratumoral CXCR5+CD8+T cell infiltration are more likely to benefit from adjuvant chemotherapy. Microsatellite-unstable and Epstein–Barr virus positive tumors are enriched with CXCR5+CD8+T cells. Gastric cancer infiltrating CXCR5+CD8+T cells represent a specific subtype of stem-like CD8+T with effector memory feature. Identification of the clinical significance and phenotype of gastric cancer infiltrating CXCR5+CD8+T provides a roadmap for patient stratification and trials of targeted therapies.

scholarly journals PD-L1 Expression Associated with Epstein—Barr Virus Status and Patients’ Survival in a Large Cohort of Gastric Cancer Patients in Northern Brazil

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3107
Author(s):  
Caroline de Fátima Aquino Moreira-Nunes ◽  
Cláudia Nazaré de Souza Almeida Titan Martins ◽  
Danielle Feio ◽  
Isamu Komatsu Lima ◽  
Leticia Martins Lamarão ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Survival Data ◽  
Epstein Barr Virus ◽  
Gastric Neoplasms ◽  
Probability Of Survival ◽  
Barr Virus ◽  
Kaplan Meier ◽  
Epstein Barr ◽  
Gastric Cancer Patients

Gastric cancer (GC) is a worldwide health problem, making it one of the most common types of cancer, in fifth place of all tumor types, and the third highest cause of cancer deaths in the world. There is a subgroup of GC that consists of tumors infected with the Epstein–Barr virus (EBV) and is characterized mainly by the overexpression of programmed cell death protein-ligand-1 (PD-L1). In the present study, we present histopathological and survival data of a thousand GC patients, associated with EBV status and PD-L1 expression. Of the thousand tumors analyzed, 190 were EBV-positive and the vast majority (86.8%) had a high relative expression of mRNA and PD-L1 protein (p < 0.0001) in relation to non-neoplastic control. On the other hand, in EBV-negative samples, the majority had a low PD-L1 expression of RNA and protein (p < 0.0001). In the Kaplan–Meier analysis, the probability of survival and increased overall survival of EBV-positive GC patients was impacted by the PD-L1 overexpression (p < 0.0001 and p = 0.004, respectively). However, the PD-L1 low expression was correlated with low overall survival in those patients. Patients with GC positive for EBV, presenting PD-L1 overexpression can benefit from immunotherapy treatments and performing the quantification of PD-L1 in gastric neoplasms should be adopted as routine.

scholarly journals Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis

2014 ◽  
Vol 20 (14) ◽  
pp. 1825-1832 ◽  
Author(s):  
Michael P Pender ◽  
Peter A Csurhes ◽  
Casey MM Pfluger ◽  
Scott R Burrows
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Clinical Course ◽  
Effector Memory ◽  
Barr Virus ◽  
Effector Memory T Cells ◽  
The Central Nervous System ◽  
Epstein Barr

Background: Patients with multiple sclerosis (MS) have a deficiency of circulating CD8+ T cells, which might impair control of Epstein–Barr virus (EBV) and predispose to MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. Based on the expression of CD45RA and CD62L, CD4+ T cells and CD8+ T cells can be subdivided into four subsets with distinct homing and functional properties, namely: naïve, central memory, effector memory (EM) and effector memory re-expressing CD45RA (EMRA) cells. Objective: Our aim was to determine which memory subsets are involved in the CD8+ T cell deficiency and how these relate to clinical course. Methods: We used flow cytometry to analyze the memory phenotypes of T cells in the blood of 118 MS patients and 112 healthy subjects. Results: MS patients had a decreased frequency of EM (CD45RA–CD62L–) and EMRA (CD45RA+CD62L–) CD8+ T cells, which was present at the onset of disease and persisted throughout the clinical course. The frequencies of CD4+ EM and EMRA T cells were normal. Conclusion: Deficiency of effector memory CD8+ T cells is an early and persistent feature of MS and might underlie the impaired CD8+ T cell control of EBV.

scholarly journals Case Report: Epstein-Barr virus Positive Gastric Carcinoma

2019 ◽  
pp. 145-151
Author(s):  
Gasenko E ◽  
Hegmane A ◽  
Plate S ◽  
Zvirbule Z ◽  
Elsberga E ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Epstein Barr Virus ◽  
Symptom Control ◽  
Locally Advanced ◽  
Disease Stabilisation ◽  
The Cancer Genome Atlas ◽  
Barr Virus ◽  
Potential Biomarker ◽  
Epstein Barr

In 2014, The Cancer Genome Atlas provided a molecular classification defining Epstein-Barr virus (EBV)-positive gastric cancer as a separate subtype. While its prognostic role is still debatable, emerging potential biomarker role for personalized treatment strategies is already recognized by international guidelines. We report a case with successful combined therapy of a 64-year-old EBV-positive gastric cancer male patient. Patient initially presented with locally advanced gastric cancer, which was treated surgically; three years later patient developed recurrence within the remnant stomach and was treated surgically. Two years after operation patient developed distant metastases and was enrolled in a clinical trials’ (NCT01630083) arm 2: receiving chemotherapy and monoclonal antibody claudiximab. This treatment induced durable disease stabilisation for 34 months. After progression, second line chemotherapy with docetaxel and cisplatin provided additional disease stabilisation and symptom control for 8 months. Patient’s overall survival reached 9.1 years. Presented report shows EBV- ositive gastric cancer case with better overall survival compared to reported average, which contributes to the meaningfulness of its distinction as a separate subtype, evidence that targeted therapy is more effective in selected patient groups, and EBV as an emerging biomarker.

Fas Down-Modulation in Epstein Barr Virus (EBV)-Specific Cytotoxic T-Lymphocytes (CTLs) Reduces Their Sensitivity to Fas/Fasl-Induced Apoptosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2647-2647
Author(s):  
Gianpietro Dotti ◽  
Barbara Savoldo ◽  
Martin Pule ◽  
Karin C. Straathof ◽  
Ettore Biagi ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Antigen ◽  
Epstein Barr Virus ◽  
Genetically Modified ◽  
Effector Memory ◽  
Antigen Specificity ◽  
Barr Virus ◽  
Specific Ctls ◽  
Epstein Barr

Abstract Adoptive immunotherapy with Epstein Barr Virus (EBV)-specific CTL has been successfully used to treat patients with EBV related malignancies including Post Transplant Lymphoproliferative disorder, Hodgkin’s lymphoma and Nasopharyngeal carcinoma. However, these and other potentially immunogenic tumors have evolved evasion strategies that subvert the effectiveness of the immune response. One such strategy involves expression of FasL, which likely impedes the host immune response by accelerating the apoptotic death of Fas-expressing tumor infiltrating T-cells. EBV-specific CTLs, like most effector memory T cells express high levels of Fas and are highly sensitive to cross-linking of the ligand. We therefore determined whether EBV-specific CTLs could be genetically modified to resist FasL-mediated immune evasion. We used retroviral siRNA (pSUPER.retro) directed against the Fas gene product to knockdown receptor expression in tumor-antigen specific CTLs. Transduction of CTLs with siRNA targeting Fas mRNA significantly knocked down Fas expression compared to control cells (Fas MFI 107 ± 47 vs. 402 ± 47, p&lt;0.001). This effect was paralleled by a significant reduction of apoptosis induced by the Fas agonistic antibody (clone CH-11) in modified CTLs compared to control cells (23% ± 3% vs. 44% ± 7% p=0.006). Fas down-modulation was stable over time in CTLs modified, and addition of CH-11 antibody to the culture selected a uniformly Faslow CTL population (Fas MFI 79 ± 29) that was entirely resistant to FasL mediated lysis. However, germ line deletions as well as function-impairing mutations of Fas and FasL can induce T-lymphoproliferation and autoimmune diseases. We therefore compared the growth characteristics and the antigen specificity of unmodified and Fas knockdown CTLs. Survival and proliferation of genetically modified CTLs remain completely dependent on antigen specific stimulation and the presence of other physiological growth signals. Moreover, as assessed by the analysis of the Vb TcR repertoire, IFN-g-release (Elispot) and tetramer staining the modified CTLs remained polyclonal and conserved their antigen specificity. These data suggest that responsiveness to this single death signal may be removed from an effector-memory population of CTLs without adversely affecting their safety. Tumor-antigen-specific CTLs with lower expression of Fas receptor should have a selective functional and survival advantage over unmodified CTLs in the presence of tumors expressing FasL, and may be of value for adoptive cellular therapy of such malignancies.

A pilot study of avelumab in Epstein-Barr virus-associated gastric cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS473-TPS473
Author(s):  
Ronan Andrew Mc Laughlin ◽  
John Aird ◽  
Orla McCormack ◽  
C. DeGascun ◽  
R. Hussein ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Pilot Study ◽  
Epstein Barr Virus ◽  
Single Agent ◽  
The Cancer Genome Atlas ◽  
Eligibility Criteria ◽  
Barr Virus ◽  
Stage 4 ◽  
Epstein Barr

TPS473 Background: Gastric Cancer (GC) is the third most common cause of cancer related deaths worldwide. The median overall survival of patients with stage 4 disease is approximately 1 year. Current accepted treatment approach with chemotherapy is applied with little consideration for known genetic or biologic heterogeneity. Whilst immune-based approaches in GC look promising it is clear that single-agent PD1/PDL1 inhibition benefit a minority. We must clarify a means of identifying prospectively those patients who may benefit from this treatment. A recent landmark paper by The Cancer Genome Atlas (TCGA) proposed a classification of GC into four subtypes: Epstein-Barr-virus (EBV)-positive, microsatellite instable (MSI), chromosomal instable (CI), and genomically stable (GS). Two of the four – EBV and MSI subtypes – are likely to be immunogenic and amenable to PD1/PDL1 inhibition. Recent advances have shown EBV-positive tumors to be infiltrated by lymphocytes and be enriched for PDL1. Methods: This single centre single-arm pilot study in gastric or junctional adenocarcinoma will explore the hypothesis that administering anti-PDL1 therapy (Avelumab) in a prospectively identified population enriched for potential responders will result in improved outcomes. The anticipated frequency of EBV associated-GC (c10%) means that approximately N = 100 patients will be screened to identify N = 10 participants. If a positive signal for efficacy is seen this will provide a basis for a larger, multicentre study. Previously treated Patients with confirmation of stage 4 EBV- positive gastric or oesophago-gastric adenocarcinoma meeting eligibility criteria will be enrolled. Avelumab will be administered at a dose of 10mg/kg IV every 14days. Primary endpoint is to determine the 6-month progression free survival (PFS) of Avelumab in EBV-associated GC. Secondary endpoints include overall response rate, overall survival, median PFS time and feasibility/accrual rate at 12 months. Exploratory endpoints will be to evaluate changes in immune parameters in the peripheral blood over time. Kaplan-Meier methods for primary efficacy endpoint with two-tailed one-sample proportion test will be used to evaluate the evidence to reject the null hypothesis. Clinical trial information: 2018-002085-39.

scholarly journals Comprehensive Multi-Omics Analysis Reveals Aberrant Metabolism of Epstein–Barr-Virus-Associated Gastric Carcinoma

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1220 ◽  
Author(s):  
Yoon ◽  
Kim ◽  
Long ◽  
Min ◽  
Kim ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Carcinoma ◽  
Epstein Barr Virus ◽  
Tissue Samples ◽  
Barr Virus ◽  
Advanced Gastric Carcinoma ◽  
Metabolic Genes ◽  
Epithelial Cell Lines ◽  
Epstein Barr ◽  
Gastric Cancer Patients

The metabolic landscape of Epstein–Barr-virus-associated gastric cancer (EBVaGC) remains to be elucidated. In this study, we used transcriptomics, metabolomics, and lipidomics to comprehensively investigate aberrant metabolism in EBVaGC. Specifically, we conducted gene expression analyses using microarray-based data from gastric adenocarcinoma epithelial cell lines and tissue samples from patients with clinically advanced gastric carcinoma. We also conducted complementary metabolomics and lipidomics using various mass spectrometry platforms. We found a significant downregulation of genes related to metabolic pathways, especially the metabolism of amino acids, lipids, and carbohydrates. The effect of dysregulated metabolic genes was confirmed in a survival analysis of 3951 gastric cancer patients. We found 57 upregulated metabolites and 31 metabolites that were downregulated in EBVaGC compared with EBV-negative gastric cancer. Sixty-nine lipids, mainly ether-linked phospholipids and triacylglycerols, were downregulated, whereas 45 lipids, mainly phospholipids, were upregulated. In total, 15 metabolisms related to polar metabolites and 15 lipid-associated pathways were involved in alteration of metabolites by EBV in gastric cancer. In this work, we have described the metabolic landscape of EBVaGC at the multi-omics level. These findings could help elucidate the mechanism of EBVaGC oncogenesis.

scholarly journals Distinct memory CD4+ T-cell subsets mediate immune recognition of Epstein Barr virus nuclear antigen 1 in healthy virus carriers

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1138-1146 ◽  
Author(s):  
Kevin N. Heller ◽  
Jenica Upshaw ◽  
Beza Seyoum ◽  
Henry Zebroski ◽  
Christian Münz
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Epstein Barr Virus ◽  
T Cell Subsets ◽  
Nuclear Antigen ◽  
Effector Memory ◽  
Immune Recognition ◽  
T Helper 1 ◽  
Barr Virus ◽  
Epstein Barr

AbstractCD4+ T cells, specific for transforming latent infection with the Epstein Barr virus (EBV), consistently recognize the nuclear antigen 1 of EBV (EBNA1). EBNA1-specific effector CD4+ T cells are primarily T-helper 1 (TH1) polarized. Here we show that most healthy EBV carriers have such IFN-secreting EBNA1-specific CD4+ T cells at a frequency of 0.03% of circulating CD4+ T cells. In addition, healthy carriers have a large pool of CD4+ T cells that proliferated in response to EBNA1 and consisted of distinct memory-cell subsets. Despite continuous antigen presence due to persistent EBV infection, half of the proliferating EBNA1-specific CD4+ T cells belonged to the central-memory compartment (TCM). The remaining EBNA1-specific CD4+ T cells displayed an effector-memory phenotype (TEM), of which a minority rapidly secreted IFN upon stimulation with EBNA1. Based on chemokine receptor analysis, all EBNA1-specific TCM CD4+ T cells were TH1 committed. Our results suggest that protective immune control of chronic infections, like EBV, includes a substantial reservoir of TCM CD4+ TH1 precursors, which continuously fuels TH1-polarized effector cells.

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