| Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC:~100%) and gastric carcinoma (GC: ~10%). Previous data by others have linked EBV to a subset of breast cancer, but we demonstrated this to be an error due to use of a monoclonal antibody, cross-reactive between EBNA1 and MAGE- 4 1 . In a comprehensive study of >550 cases we found that 7.3% of GC in the Netherlands is EBV-positive, with active viral gene expression in the tumour cells 2 . Our data indicate that EBV+ GC should be considered as a distinct disease entity, with different localization, demographics, less lymph node involvement and a better prognosis. EBV+ GC shows expression of LMP2 and BARF1, an EBV-encoded carcinoma-specific oncogene, that appears to be secreted by the carcinoma cells 3 . We developed BARF1-specific antibodies and created a BARF1 capture ELISA for detection of BARF1 in body fluids. Using immunohistochemistry, we were unable to demonstrate BARF1protein expression in human tumor sections in vivo, which were BARF1-mRNA positive 4 . Using purified recombinant BARF1 protein we observed a ack of anti-BARF1 antibody responses in EBV+ tumour bearing patients, nor in healthy EBV carriers and patients with acute EBV infection, despite strong response to other EBV antigens 4 . It seems that BARF1, -like the EBV oncogen LMP1-, selectively escapes immune recognition. On the other hand in EBV+ GC patients we found increased local inflammation with activated CD8+ lymphocytic infiltrate, correlating with less lymph node involvement and better prognosis 5 . This suggests a role for cellular immune defences in controlling metastatic outgrowth. EBV-encoded LMP2 protein, expressed at high levels in EBV+GC at the RNA level, could be the responsible target, opening options for immunotherapy. We recently made new LMP2-specific monoclonal antibodies and LMP2 expression vectors to further analyse this option. In contrast to NPC EBV+GC lacks LMP1 expression. LMP1 creates an immunosuppressive milieu around the tumor cells. In NPC, LMP1 is expressed abundantly in most cases 6 . We showed that LMP1 is secreted from NPC tumor cells as MHC-II rich exosomes, similar as we found for EBV+ B-cells 7 . EBV-LMP1 selectively suppresses T-cell reactivity and we located the functional domain to the evolutionary conserved first transmembrane domain 8 . We aim to further study the role of EBV gene-products in oncogenesis and immune escape. We created a human epithelial expression system for studying BARF1 function and an inducible LMP1 expression system for analysing LMP1-exosome association . Two new KWF projects were granted to support this work. |
