Overexpression and gene amplification of PD-L1 in cancer cells and PD-L1+ immune cells in Epstein–Barr virus-associated gastric cancer: the prognostic implications

BackgroundEpstein–Barr virus-associated gastric cancer(EBVaGC)has a unique tumor immune microenvironment. We performed a comprehensive analysis of the tumor-infiltrating immune cells in a cohort of EBVaGC in a Chinese population.MethodsEpstein–Barr encoding region (EBER) in situ hybridization was performed in 1,328 consecutive cases of surgically resected GC. Densities of immune cells, including T cells, B cells, natural killer cells, and macrophages from the patients were calculated after immunohistochemical staining with CD3, CD20, CD57, and CD68 antibodies in tissue microarrays, respectively.ResultsEBVaGC patients accounted for 4.1% (55 of 1,328) cases in the overall population. The average age of patients with EBVaGC was lower than that of non-EBVaGC patients. Histologically, EBVaGC patients exhibited poorly differentiated adenocarcinoma (P = 0.004) and lower frequency of vascular invasion (P = 0.034). The density of CD3+ T lymphocytes (CD3, 23.84 ± 14.49 vs. 12.76 ± 8.93, P < 0.001) and CD68+ macrophages (CD68, 9.73 ± 5.25 vs. 5.44 ± 4.18, P < 0.001) was significantly higher in EBVaGC patients. CD3+ T cell density predicted better 5-year overall survival of EBVaGC patients (P = 0.022).ConclusionsEBVaGC patients were younger with low-differentiated adenocarcinoma and less vascular invasion. Increased infiltration of multiple immune cells affected the prognosis of patients, especially EBVaGC patients with more CD3+ T lymphocytes, who survived longer.

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Genome-wide identification of Epstein-Barr virus-driven promoter methylation profiles of human genes in gastric cancer cells

Cancer ◽

10.1002/cncr.27724 ◽

2012 ◽

Vol 119 (2) ◽

pp. 304-312 ◽

Cited By ~ 81

Author(s):

Junhong Zhao ◽

Qiaoyi Liang ◽

Kin-Fai Cheung ◽

Wei Kang ◽

Raymond W. M. Lung ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Promoter Methylation ◽

Epstein Barr Virus ◽

Gastric Cancer Cells ◽

Barr Virus ◽

Genome Wide ◽

Human Genes ◽

Epstein Barr

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LY294002 may overcome 5-FU resistance via down-regulation of activated p-AKT in Epstein-Barr virus-positive gastric cancer cells

BMC Cancer ◽

10.1186/1471-2407-10-425 ◽

2010 ◽

Vol 10 (1) ◽

Cited By ~ 49

Author(s):

Jung-Young Shin ◽

Jeong-Oh Kim ◽

Suk Kyeong Lee ◽

Hiun-Suk Chae ◽

Jin-Hyoung Kang

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Epstein Barr Virus ◽

Gastric Cancer Cells ◽

Down Regulation ◽

Barr Virus ◽

Epstein Barr

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Epstein-Barr virus-specific methylation of human genes in gastric cancer cells

Infectious Agents and Cancer ◽

10.1186/1750-9378-5-27 ◽

2010 ◽

Vol 5 (1) ◽

pp. 27 ◽

Cited By ~ 40

Author(s):

Julie L Ryan ◽

Richard J Jones ◽

Shannon C Kenney ◽

Ashley G Rivenbark ◽

Weihua Tang ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Epstein Barr Virus ◽

Gastric Cancer Cells ◽

Barr Virus ◽

Human Genes ◽

Epstein Barr

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Olaparib-induced Apoptosis Through EBNA1-ATR-p38 MAPK Signaling Pathway in Epstein-Barr Virus-positive Gastric Cancer Cells

Anticancer Research ◽

10.21873/anticanres.15513 ◽

2021 ◽

Vol 42 (1) ◽

pp. 555-563

Author(s):

SUNG HO MOON ◽

NAM-SOOK PARK ◽

MIN HYE NOH ◽

YEONG SEOK KIM ◽

SOON HO CHEONG ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

P38 Mapk ◽

Epstein Barr Virus ◽

Mapk Signaling ◽

Gastric Cancer Cells ◽

Barr Virus ◽

Epstein Barr ◽

Induced Apoptosis

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The clinicopathological significance and predictive value for immunotherapy of programmed death ligand-1 expression in Epstein-Barr virus-associated gastric cancer

OncoImmunology ◽

10.1080/2162402x.2021.1938381 ◽

2021 ◽

Vol 10 (1) ◽

pp. 1938381

Author(s):

Xiao-Li Wei ◽

Qian-Wen Liu ◽

Fu-Rong Liu ◽

Sha-Sha Yuan ◽

Xiao-Fen Li ◽

...

Keyword(s):

Gastric Cancer ◽

Predictive Value ◽

Epstein Barr Virus ◽

Programmed Death Ligand 1 ◽

Barr Virus ◽

Programmed Death ◽

Clinicopathological Significance ◽

Epstein Barr

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

Nature Communications ◽

10.1038/s41467-021-23356-w ◽

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.

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Identification of differential proteomics in Epstein-Barr virus-associated gastric cancer and related functional analysis

Cancer Cell International ◽

10.1186/s12935-021-02077-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zeyang Wang ◽

Zhi Lv ◽

Qian Xu ◽

Liping Sun ◽

Yuan Yuan

Keyword(s):

Gastric Cancer ◽

Functional Analysis ◽

Protein Expression ◽

Epstein Barr Virus ◽

Protein Profile ◽

Expression Patterns ◽

Clinicopathological Parameters ◽

Differential Proteomics ◽

Barr Virus ◽

Epstein Barr

Abstract Background Epstein-Barr virus-associated gastric cancer (EBVaGC) is the most common EBV-related malignancy. A comprehensive research for the protein expression patterns in EBVaGC established by high-throughput assay remains lacking. In the present study, the protein profile in EBVaGC tissue was explored and related functional analysis was performed. Methods Epstein-Barr virus-encoded RNA (EBER) in situ hybridization (ISH) was applied to EBV detection in GC cases. Data-independent acquisition (DIA) mass spectrometry (MS) was performed for proteomics assay of EBVaGC. Functional analysis of identified proteins was conducted with bioinformatics methods. Immunohistochemistry (IHC) staining was employed to detect protein expression in tissue. Results The proteomics study for EBVaGC was conducted with 7 pairs of GC cases. A total of 137 differentially expressed proteins in EBV-positive GC group were identified compared with EBV-negative GC group. A PPI network was constructed for all of them, and several proteins with relatively high interaction degrees could be the hub genes in EBVaGC. Gene enrichment analysis showed they might be involved in the biological pathways related to energy and biochemical metabolism. Combined with GEO datasets, a highly associated protein (GBP5) with EBVaGC was screened out and validated with IHC staining. Further analyses demonstrated that GBP5 protein might be associated with clinicopathological parameters and EBV infection in GC. Conclusions The newly identified proteins with significant differences and potential central roles could be applied as diagnostic markers of EBVaGC. Our study would provide research clues for EBVaGC pathogenesis as well as novel targets for the molecular-targeted therapy of EBVaGC.

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Immunotherapy for Esophageal and Gastric Cancer

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_175231 ◽

2017 ◽

pp. 292-300 ◽

Cited By ~ 1

Author(s):

Ronan J. Kelly

Keyword(s):

Gastric Cancer ◽

Tumor Cells ◽

Immune Cells ◽

Single Agent ◽

Phase Iii ◽

Immune Checkpoints ◽

Barr Virus ◽

Mutation Burden ◽

Heavily Pretreated ◽

Epstein Barr

PD-L1 upregulation occurs in approximately 40% of gastroesophageal cancers. However, unlike other solid tumors, there is minimal PD-L1 expressed on the cancer cells; rather, expression occurs predominantly on infiltrating myeloid cells. Preliminary clinical data involving single-agent PD-1/PD-L1 inhibitors in metastatic gastroesophageal cancer have reported response rates of 22%–27% for patients with PD-L1+ tumors and 10%–17% for unselected patients. The phase III ONO-4538-12 (ATTRACTION 2) trial has demonstrated an improved overall survival for nivolumab compared with placebo for patients with heavily pretreated gastric cancer. In the future, we will need better biomarkers to select those most likely to respond and/or identify patients who may need combination immunotherapeutics or alternate strategies. A number of subsets of gastric cancer with different immune signatures, most notably tumors positive for Epstein-Barr virus and microsatellite instability, have been identified, with approximately 50% and 94% PD-L1+ staining seen on tumor cells and immune cells in the EBV subtype and approximately 33% and 45% PD-L1+ staining seen on tumor cells and immune cells in MSI high tumors. Both subtypes demonstrate PD-L1+ immune cells with tumor-infiltrating patterns, unlike the more commonly seen PD-L1+ immune cells at the invasive margin. PD-L2 expression has been reported in 52% of esophageal adenocarcinomas but little is known about the expression of other immune checkpoints. Additional factors that suggest gastroesophageal cancers may respond to checkpoint inhibition include the high somatic mutation burden and the link with chronic inflammation. Here we provide a comprehensive review of the checkpoint inhibitor data published to date in advanced esophagogastric cancers and rationalize how the immune microenvironment in these diverse tumors can explain response or resistance to immunotherapeutics.

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