Abstract
Epstein-Barr virus-associated gastric cancer (EBVaGC) has been proposed to be a distinct subtype with a specific immune microenvironment. Here, we evaluated tumor-infiltrating T-cell subsets and the expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in 571 gastric cancers (GCs).Tissue microarrays were stained using EBER in situ hybridization for EBV and using immunohistochemistry for CD4, CD8, Foxp3, PD-1 and PD-L1. GCs were categorized into four types based on CD8+ infiltration and PD-L1 expression. The 5-year overall survival (OS) was evaluated according to EBV infection, T-cell subsets, PD-1 and PD-L1 expression and immune types.Thirty-two (5.3%) EBVaGCs were identified, which were more prevalent for CD8+ (p<0.001) and Foxp3+ (p=0.020) cell infiltration than EBV-negative GCs (EBVnGCs), suggesting a better 5-year OS (p=0.003). CD8+ (p=0.001) and Foxp3+ (p=0.018) cell infiltration was associated with better 5-year OS, whereas PD-L1 expression correlated with a poor 5-year OS (p=0.002). EBVaGC and EBVnGC had heterogeneous immune microenvironment, with CD8+ PD-L1− GC exhibiting the best 5-year OS (p<0.001).GC was an immune ignorant dominant tumor and poor to no T-cell infiltration. An immune type classification algorithm can provide prognostic information and a rational basis for immunotherapy.
Highlights
Epstein-Barr virus (EBV) is a member of the Herpesviridae family that latently infect greater more than90% of adults worldwide and is associated with several human malignancies, such as Hodgkin's lymphoma, Burkitt's lymphoma, nasal NK/T-cell lymphoma, nasopharyngeal carcinoma and a subset of gastric www.impactjournals.com/oncotarget cancer (GC) [1]
There was no significant difference in gender, American Joint Committee on Cancer (AJCC) stage, tumor location, depth, histological classification and differentiation between EBV-associated GC (EBVaGC) and EBV-negative GC (EBVnGC)
The lower frequency of EBV infection in our study might be because of geographical and environmental factors [3, 10, 11], and EBV infection was associated with younger age
Summary
Epstein-Barr virus (EBV) is a member of the Herpesviridae family that latently infect greater more than90% of adults worldwide and is associated with several human malignancies, such as Hodgkin's lymphoma, Burkitt's lymphoma, nasal NK/T-cell lymphoma, nasopharyngeal carcinoma and a subset of gastric www.impactjournals.com/oncotarget cancer (GC) [1]. Based on the presence or absence of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression, four tumor immune microenvironment types have been proposed [9], including type I (TILs+ PDL1+ associated with adaptive immune resistance), type II (TILs- PD-L1- indicating immune ignorance), type III (TILs- PD-L1+ indicating intrinsic induction) and type IV (TILs+ PD-L1- indicating other suppressors promoting immune tolerance). To some extent, this stratification has prognostic value and indicates possible cancer immunotherapy strategies
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