Abstract
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.
Highlights
4–18% of the cases of gastric cancer (GC) are caused by Epstein–Barr virus (EBV) (1)
EBVassociated gastric cancer (EBVaGC) was frequently found in patients
Differentiated cancer was more frequent in EBVaGC patients (6.3 vs. 2.7 vs. 0.0%, P = 0.004, Table 1) and adenocarcinoma was more frequent than Ring cell carcinoma (4.5 vs 0.0%, P = 0.029, Table 1)
Summary
4–18% of the cases of gastric cancer (GC) are caused by Epstein–Barr virus (EBV) (1). The molecular characteristics of EBV-positive gastric cancer were summarized and attributed to mutation of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), overexpression of programmed death-ligand 1 and 2 (PD-L1/2), EBV-CIMP (CpG island methylator phenotype), silencing of cyclin dependent kinase inhibitor 2A (CDKN2A) (p16INK4A), and immune cell signaling (2). In patients with EBV-positive tumors, dramatic responses to pembrolizumab were observed (objective response rate of 100% in EBVaGC), which might be related to EBVaGC-rich immune cell infiltration and increased expression of immune checkpoint pathway genes (3–5). Analysis of the immune microenvironment of EBVaGC is necessary. Epstein–Barr virus-associated gastric cancer(EBVaGC)has a unique tumor immune microenvironment. We performed a comprehensive analysis of the tumorinfiltrating immune cells in a cohort of EBVaGC in a Chinese population
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