PD-L1 overexpression in EBV-positive gastric cancer is caused by unique genomic or epigenomic mechanisms

Nakano, Hiroshi; Saito, Motonobu; Nakajima, Shotaro; Nakayama, Yuko; Kase, Koji; Yamada, Leo; Kanke, Yasuyuki; Hanayama, Hiroyuki; Onozawa, Hisashi; Okayama, Hirokazu; Fujita, Shotaro; Sakamoto, Wataru; Saze, Zenichiro; Momma, Tomoyuki; Mimura, Kosaku; Ohki, Shinji; Goto, Akiteru; Kono, Koji

doi:10.1038/s41598-021-81667-w

Cited by 31 publications

(30 citation statements)

References 32 publications

(63 reference statements)

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“…Recently, Ge and colleagues found that EBV-encoded circular RNA CircBART2.2 upregulated the expression of PD-L1 in NPC and further inhibited the T-cell function ( 36 ). In other malignancies with positive EBV infection, IFN-gamma mediated signaling pathways, EBV microRNA, somatic gene mutations, and epigenetic modifications were also reported to regulate PD-L1 expression ( 45 , 46 ). Therefore, PD-L1 may be an effective target for immunotherapy as well as a useful biomarker for predicting metastasis and survival.…”

Section: Discussionmentioning

confidence: 99%

Combined Association of Tumoral PD-L1 Expression and Pretreatment Presence of Epstein-Barr Virus DNA With Risk Stratification and Prognosis of Patients With Nasopharyngeal Carcinoma

Peng

Zhao

et al. 2022

Front. Oncol.

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BackgroundLittle is known about whether the combination of tumor programmed death-ligand 1 (PD-L1) expression and pretreatment EBV DNA status can help stratify nasopharyngeal carcinoma (NPC) patients by risk of metastasis or predict prognosis.MethodsPD-L1 expression was assessed using immunohistochemical staining of 78 non-keratinizing NPC patients with clinical data. Survival outcomes and independent prognostic factors were identified.ResultsSeventy-eight patients were included, high PD-L1 expression was observed in 25 of 43 patients (58%) with metastasis, while it was observed only in 7 of 35 patients (20%) without metastasis. Multivariate analyses showed that progression-free survival (PFS) was independently predicted by tumoral PD-L1 expression and pretreatment EBV DNA status. When combining, 93.75% patients with high PD-L1 and EBV infection developed distant metastasis, and those patients were associated with worse PFS.ConclusionsBoth PD-L1 expression and pretreatment EBV DNA are closely related to metastasis and prognosis of NPC patients. Their combination can facilitate risk stratification and prognosis prediction, which may improve disease treatment and management.

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Section: Discussionmentioning

confidence: 99%

Combined Association of Tumoral PD-L1 Expression and Pretreatment Presence of Epstein-Barr Virus DNA With Risk Stratification and Prognosis of Patients With Nasopharyngeal Carcinoma

Peng

Zhao

et al. 2022

Front. Oncol.

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“…However, previous studies have demonstrated an overexpression of PD-L1 in EBV-positive GC. 55 , 63 Indeed, a combined analysis of 4 studies involving 1307 Japanese patients indicated a significant association between EBV positivity and PD-L1 expression ( p < .0001). 10 Similar findings have also been reported in studies from Japan.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan

Yoshida

Ogura

Tanabe

et al. 2022

Cancer Biology & Therapy

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This real-world study examined the prevalence of programmed death ligand-1 (PD-L1) expression and assessed the frequency of microsatellite instability-high (MSI-H) status and Epstein-Barr virus (EBV) positivity in Japanese patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. This multicenter (5 sites), retrospective, observational study (November 2018–March 2019) evaluated Japanese patients with advanced gastric and GEJ adenocarcinoma after surgical resection (Stage II/III at initial diagnosis) or unresectable advanced cancer (Stage IV). The primary objectives were prevalence of PD-L1 expression (combined positive score [CPS] ≥1), MSI status, and EBV positivity. Tumor specimens of 389/391 patients were analyzed (male, 67.1%; mean age, 67.6 ± 12.2 years); 241/389 (62%) were PD-L1 positive, 24/379 (6.3%) had MSI-H tumors, and 13/389 (3.3%) were EBV positive. PD-L1 expression was higher in tumor-infiltrating immune cells than in tumor cells for lower CPS cutoffs. Among patients with MSI-H tumors and EBV-positive tumors, 19/24 (79.2%) and 9/13 (69.2%), respectively, were PD-L1 positive. A greater proportion of patients with MSI-H tumors (83.3% [20/24]) were PD-L1 positive than those with MSI-low/stable tumors (60.8% [216/355]; p = .0297); similarly, an association was observed between history of H pylori infection and PD-L1 expression. A higher proportion of patients with MSI-H tumors demonstrated PD-L1 expression with a CPS ≥10 (66.7% [16/24]) vs those with MSI-low/stable tumors (24.8% [88/355]; p < .0001). The prevalence of PD-L1 positivity among Japanese patients was comparable to that in previous pembrolizumab clinical trials and studies in gastric cancer. Particularly, higher PD-L1 expression was observed in MSI-H tumors.

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“…This is in line with reports demonstrating an induction of PD-L1 upon EBV infection with an involvement of LMP1. 74 , 75 …”

Section: Discussionmentioning

confidence: 99%

Novel approach to identify putative Epstein–Barr–virus microRNAs regulating host cell genes with relevance in tumor biology and immunology

et al. 2022

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The human Epstein–Barr virus is associated with several human solid and hematopoietic malignancies. However, the underlying molecular mechanisms including virus-encoded microRNAs (miRs), which lead to the malignant transformation of infected cells and immune evasion of EBV-associated tumors, have not yet been characterized. The expression levels of numerous known EBV-specific miRs and their suitability as diagnostic and/or prognostic markers were determined in different human EBV-positive tissues followed by in silico analyses to identify putative EBV-miR-regulated target genes, thereby offering a suitable screening strategy to overcome the limited available data sets of EBV-miRs and their targeted gene networks. Analysis of microarray data sets from healthy human B cells and malignant-transformed EBV-positive B cells of patients with Burkitt’s lymphoma revealed statistically significant (p < 0.05) deregulated genes with known functions in oncogenic properties, immune escape and anti-tumoral immune responses. Alignments of in vivo and in silico data resulted in the prediction of putative candidate EBV-miRs and their target genes. Thus, a combinatorial approach of bioinformatics, transcriptomics and in situ expression analyses is a promising tool for the identification of EBV-miRs and their potential targets as well as their eligibility as markers for EBV detection in different EBV-associated human tissue.

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PD-L1 overexpression in EBV-positive gastric cancer is caused by unique genomic or epigenomic mechanisms

Cited by 31 publications

References 32 publications

Combined Association of Tumoral PD-L1 Expression and Pretreatment Presence of Epstein-Barr Virus DNA With Risk Stratification and Prognosis of Patients With Nasopharyngeal Carcinoma

Combined Association of Tumoral PD-L1 Expression and Pretreatment Presence of Epstein-Barr Virus DNA With Risk Stratification and Prognosis of Patients With Nasopharyngeal Carcinoma

Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan

Novel approach to identify putative Epstein–Barr–virus microRNAs regulating host cell genes with relevance in tumor biology and immunology

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