Differentiated tumor immune microenvironment of Epstein-Barr virus-associated and negative gastric cancer: implication in prognosis and immunotherapy

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.