Immunophenotypic characterization of Epstein-Barr virus-associated gastric carcinoma: massive infiltration by proliferating CD8+ T-lymphocytes.

A subset of gastric carcinoma carries Epstein-Barr virus (EBV). The immunophenotypic features of EBV-associated (EBV+) gastric carcinoma, which we have analyzed using 25 EBV+ cases, remain unclear. Frozen tissue samples were stained with antibodies to various immune cell markers. To evaluate the proliferative activity of CD8+ cells, we performed CD8/Ki-67 double staining on paraffin-embedded sections. The results were compared with those in EBV-negative (EBV-) gastric carcinomas. All EBV+ and EBV- gastric carcinoma cells expressed major histocompatibility complex class I, whereas major histocompatibility complex class II expression in tumor cells was more prominent in EBV+ cases. Intercellular adhesion molecule-1 and Fas/APO-1 expression was largely restricted to EBV+ cases. The lymphocytes that infiltrated EBV+ tumor nests were predominantly CD8+ T cells, many of which expressed perforin. Immunoelectron microscopy confirmed a close cell to cell contact between these CD8+ cells and carcinoma cells. CD8+ cells were CD11a+ and CD11b- by flow cytometry performed in one case. The labeling index of Ki-67, the proliferation-associated antigen, in CD8+ cells was 4 times higher in EBV+ cases than in EBV- cases. Our data suggest that these CD8+ cells, which bear a cytotoxic phenotype, are actively proliferating in close contact with EBV+ tumor cells and that the specificity of the CD8+ cells may be directed to EBV and/or cellular antigens expressed by the tumor. This is consistent with a generally favorable prognosis of EBV+ gastric carcinoma. Because the observed T-cell infiltration is insufficient to eradicate the tumor cells, certain immunosuppressive factors were speculated to allow the essentially immunogenic carcinoma cells to establish a macroscopic lesion.