The importance of Epstein-Barr virus infection in the systemic treatment of patients with gastric cancer

Pikuła, Agnieszka; Kwietniewska, Magdalena; Rawicz‐Pruszyński, Karol; Ciseł, Bogumiła; Skórzewska, Magdalena; Gęca, Katarzyna; Franciszkiewicz-Pietrzak, Kinga; Kurylcio, Andrzej; Mielko, Jerzy; Polkowski, Wojciech

doi:10.1053/j.seminoncol.2020.04.001

Cited by 9 publications

(13 citation statements)

References 75 publications

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“…2014) and in ACRG Korean cohort (23%) ( Angell et al, 2019 ). The incidence of EBV-associated GC ranged from 418% among different regions ( Pikua et al, 2020 ), our result (4.9%) is identical to the data of a recent Korean study (25/569, 4.4%) ( Cho, Kang & Kim, 2019 ) and Taiwan study (65/1248, 5.2%) ( Huang et al, 2019 ) that used the same ISH method. A review of PD-L1 expression in gastric cancer ( Vrna et al, 2018 ) showed that the percentage of PD-L1 + in the TCs ranges from 9% to 49.1% (most of the trials were performed in Asian populations), similar to our results (41.2% in TCs).…”

Section: Discussionsupporting

confidence: 88%

“…Previous studies have demonstrated a mutually exclusive relationship between GCs that were EBV-positive and deemed to have MSI (Choi et al, 2020). However, two cases representing both MSI and EBV-positive were observed in a recent study (2/287, 0.70%) (Pereira et al, 2018) and in our study (2/226, 0.88%). Previous studies have demonstrated that MSI and EBV + subtypes were separately associated with better prognoses (Sohn et al, 2017), and our result is in line with the results from Pereira et al (2018) and De Rosa et al (2018) that suggested MSS/EBV − GCs showed the worst OS compared with MSI and EBV + GCs.…”

Section: Discussioncontrasting

confidence: 76%

“…However, two cases representing both MSI and EBV-positive were observed in a recent study (2/287, 0.70%) (Pereira et al, 2018) and in our study (2/226, 0.88%). Previous studies have demonstrated that MSI and EBV + subtypes were separately associated with better prognoses (Sohn et al, 2017), and our result is in line with the results from Pereira et al (2018) and De Rosa et al (2018) that suggested MSS/EBV − GCs showed the worst OS compared with MSI and EBV + GCs. The potential mechanism underlying better survival of these two GC subtypes is that intense inflammatory infiltration observed in EBV-positive and MSI GCs may play an important role in antitumor effects.…”

Section: Discussioncontrasting

confidence: 60%

“…2014) and adaptive immune resistance in the tumor microenvironment. Intratumor lymphocytes can release interferon-γ to induce the upregulation of PD-L1 in TCs (Pereira et al, 2018). However, the positive expression rate of PD-L1 in MSS/EBV − TCs varies greatly in different studies though there is few relevant studies, which could be attributed to the various method of PD-L1 expression determination and cut-off value of calling positive status used among different studies.…”

Section: Discussionmentioning

confidence: 99%

“…The evaluation of EBV infections were confirmed via DNA in situ hybridization (ISH-5021, ZSGB-BIO, China) using tissue microarrays (MiniCore, Alphelys, France). Tumors with brown nuclear staining were considered as EBV-positive (Pereira et al, 2018).…”

Section: Ebv In Situ Hybridizationmentioning

confidence: 99%

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Microsatellite instability and Epstein-Barr virus combined with PD-L1 could serve as a potential strategy for predicting the prognosis and efficacy of postoperative chemotherapy in gastric cancer

Yang

Jin

et al. 2021

PeerJ

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Background Microsatellite instability (MSI) and Epstein-Barr virus (EBV)-positive molecular subtypes exhibit complex immune responses in gastric cancer (GC), and PD-L1 has emerged as a prognostic biomarker associated with the cancer immune microenvironment. This study aimed to determine the prognostic value of molecular subtypes and whether the addition of PD-L1 would accurately predict the prognosis and guide postoperative chemotherapy for GC patients. Methods We performed molecular subtyping of tissue microarray slides from 226 GC patients who were treated with radical gastrectomy. The MSI status and PD-L1 expression were evaluated through immunohistochemistry (IHC) and EBV status through situ hybridization. Multiplex polymerase chain reaction (PCR) was also performed on 50 cases to validate the accuracy of IHC in defining MSI status. Differences in overall survival (OS) were assessed using the Kaplan-Meier method, log-rank test and Cox proportional hazards regression model. Results Among the 226 GC patients, 52 (23.2%) patients were classified as the MSI subtype, 11 (4.9%) were EBV+ subtype, and 161 (71.9%) were MSS (Microsatellite stable) /EBV− subtype according to TCGA analysis. Two patients were both positive for MSI and EBV infection. EBV+ cases showed higher PD-L1 positivity than MSI cases and MSS/EBV− cases (81.8% vs. 50.0% vs. 35.4%, P = 0.003). Compared with the non-MSS/EBV− (MSI or EBV+ cases) subgroup, GC patients with MSS/EBV− were associated with the worst outcomes (HR = 1.610, 95% CI [1.046–2.479], P = 0.031). MSS/EBV− GCs alone could benefit from postoperative chemotherapy (HR = 0.452, 95% CI [0.299–0.682], P < 0.001), and PD-L1-positive expression could also predict a better prognosis (HR = 0.612, 95% CI [0.389–0.962], P = 0.033) in this subgroup. Considering both chemotherapy efficacy and PD-L1 expression in the MSS/EBV− subgroup, chemotherapy could improve the prognosis for PD-L1-negative MSS/EBV− GCs (HR = 0.357, 95% CI [0.217–0.587], P < 0.001) but not PD-L1-positive MSS/EBV− GCs. Conclusions Molecular subtyping combined with PD-L1 expression could serve as a potential strategy to better predict prognosis and guide postoperative chemotherapy of GC patients.

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Section: Discussionsupporting

confidence: 88%

Section: Discussioncontrasting

confidence: 76%

Section: Discussioncontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Ebv In Situ Hybridizationmentioning

confidence: 99%

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Microsatellite instability and Epstein-Barr virus combined with PD-L1 could serve as a potential strategy for predicting the prognosis and efficacy of postoperative chemotherapy in gastric cancer

Yang

Jin

et al. 2021

PeerJ

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Perspectives for immunotherapy of EBV‐associated GLELC: A relatively “hot” tumor microenvironment

Lei,

Cao,

Zheng

et al. 2023

Cancer Medicine

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BackgroundEpstein–Barr virus (EBV)‐associated gastric lymphoepithelioma‐like carcinoma (EBVaGLELC) represents a small number of gastric cancer (GC), and research on tumor microenvironment (TME) and treatment strategy are still lacking.AimsHere, we aim to elucidate the immune features of this rare disease and further help to develop more effective treatment options.Materials & MethodsA retrospective analysis was conducted between 2019 to 2022 in West China Hospital to reveal the immunological characteristics of EBV‐positive GLELC. The difference of immune cell subset and tumor vascular structure between gastric denocarcinoma (GAC) and EBVaGLELC will be pointed out.Discussion13 patients with GELEC and 8 patients with GAC were retrospectively studied. The heterogeneity of the immune cell profile was then confirmed through multiplexed immunofluorescence staining (mIF), which revealed a higher proportion of CD3+ T cells, CD8+ T cells, and Treg cells in the EBV‐associated GLELC group. Such a distinct TME may provide therapeutic advantages, and patients with this rare subtype of GC could be good candidates for immune checkpoint inhibitors (ICIs). Angiogenesis in EBV‐positive GLELC may be less intense than that in gastric adenocarcinoma (GAC), a feature that might decrease their susceptibility to antiangiogenic therapy. Furthermore, we reported a 52‐year‐old male with advanced EBV‐positive GLELC who showed a favorable response to the combined therapy with . A repeat evaluation showed sustained partial response (PR), and the progression‐free survival (PFS) was more than 34 months until now.ConclusionCompared with GAC, EBVaGLELC revealed higher T cell infiltration and less intense of angiogenesis. It displays relatively “hot” TME that may provide the rationality to treat with immunotherapy in EBV‐related GLELC.

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LMP2A suppresses the role of AHR pathway through ERK signal pathway in EBV-associated gastric cancer

et al. 2021

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The importance of Epstein-Barr virus infection in the systemic treatment of patients with gastric cancer

Cited by 9 publications

References 75 publications

Microsatellite instability and Epstein-Barr virus combined with PD-L1 could serve as a potential strategy for predicting the prognosis and efficacy of postoperative chemotherapy in gastric cancer

Microsatellite instability and Epstein-Barr virus combined with PD-L1 could serve as a potential strategy for predicting the prognosis and efficacy of postoperative chemotherapy in gastric cancer

Perspectives for immunotherapy of EBV‐associated GLELC: A relatively “hot” tumor microenvironment

LMP2A suppresses the role of AHR pathway through ERK signal pathway in EBV-associated gastric cancer

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