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

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.

Prognostic stratification of patients with nasopharyngeal carcinoma based on tumor immune microenvironment

“…32,33 The higher PD-L1 expression in tumors, therefore, might be explained by the higher density of TILs in patients with EBV-positive NPC. Ma et al 34 previously reported that the proportion of types I and IV tumor immune microenvironments was higher, whereas that of types II and III was lower in patients with EBV-positive gastric cancer, compared with patients with EBV-negative gastric cancer. Consistent with the data for gastric cancer, 3 our study demonstrates a higher proportion of the types I and IV tumor immune microenvironments and a lower proportion of the types II and III tumor immune microenvironments in patients with EBV-positive NPC, compared with patients with EBV-negative NPC.…”

Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma

“…11 Likewise, HPV-positive head and neck squamous cell carcinoma (HNSCC) has a more extensive lymphocyte infiltrate than HPV-negative HNSCC, 12 and Epstein-Barr virus (EBV)-associated gastric cancer has a more extensive lymphoid infiltrate and higher response rate to anti-PD1 immunotherapy than EBV-negative gastric cancer. [13][14][15][16][17][18] Conversely, cancers resulting from oncogenic viruses may have lower mutational burdens than cancers that result from carcinogens, resulting in a lower number of mutation-associated neoantigens. To our knowledge, a comprehensive analysis of the tumor mutational burden and immune microenvironment for HCV, HBV, and uninfected HCC has not been reported previously.…”

Vírus Epstein-Barr, Instabilidade De Microssatélite E Expressão De Pd-L1 Nos Adenocarcinomas Gástricos: Aspectos Clínico-Patológicos E Prognósticos.

“…Para facilitar a visualização global dos parâmetros avaliados, um resumo dos resultados obtidos para cada um dos marcadores IHQ com as respectivas significâncias estatística encontram-se descritos nas tabelas 17 e 18. 59,110 Entre outras características, um maior acometimento da porção gástrica proximal e estômago remanescente após gastrectomia é com frequência associado ao CG EBV-positivo. 50 Confirmado na presente série, observamos associação entre a positividade para EBV e localização do tumor no terço proximal.…”