title: Morphological evidence of an activated cytotoxic T-cell infiltrate in EBV-positive gastric carcinoma preventing lymph node metastases.
abstract: Recently, we showed that Epstein-Barr virus (EBV)-positive gastric carcinoma (GC) forms a distinct clinicopathologic entity with a better prognosis due to lower incidence of lymph node metastases (LN+). Here we investigated whether in EBV-positive GC more pronounced activation of cellular immune responses is associated with absence of (micro)metastases. Twenty EBV-positive primary tumors (PT) (9 LN+) were matched with 28 EBV-negative GC (11 LN+) for T- and N-stage, gender, and age. The PT (n = 28) and its LNs were analyzed by EBER RNA in situ hybridization and by immunohistochemistry for MHC class I and II expression, for CD3, CD8, CD4, CD20, CD56, CD83, and Granzyme B (GzB) expression. In LN metastases of EBV-positive GC, the EBV genome is maintained, excluding tumor escape by virus deletion. All GC express MHC class I independently of EBV status. In comparison with EBV-negative GC, EBV-positive GC have higher expression of MHC class II on the tumor cells (P = 0.029) and a more extensive infiltrate (P < 0.0001) of activated GzB+ CD8+ T cells (P = 0.028), which is most abundant in those EBV-positive tumors that do not metastasize (P < 0.0001). In addition, in EBV-positive GC without metastases, the infiltrate contains higher numbers of mature dendritic cells (DC) (P = 0.018). At present, the antigenic target has to be determined. These data support the notion that local triggering of cellular immune responses in EBV-positive GC prevents lymph node metastasis formation.
authors.affiliation: Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
authors.forename: Josine
authors.initials: J
authors.lastname: van Beek
authors.forename: Axel
authors.initials: A
authors.lastname: zur Hausen
authors.forename: Sander N
authors.initials: SN
authors.lastname: Snel
authors.forename: Johannes
authors.initials: J
authors.lastname: Berkhof
authors.forename: Elma Klein
authors.initials: EK
authors.lastname: Kranenbarg
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Adriaan J C
authors.initials: AJ
authors.lastname: van den Brule
authors.forename: Jaap M
authors.initials: JM
authors.lastname: Middeldorp
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bloemena
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology* / Q000821:virology; D014408:Biomarkers, Tumor / Q000032:analysis; D020031:Epstein-Barr Virus Infections / Q000821:virology*; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000302:isolation & purification; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008207:Lymphatic Metastasis / Q000276:immunology* / Q000473:pathology; D016131:Lymphocyte Subsets / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D013274:Stomach Neoplasms / Q000276:immunology / Q000473:pathology* / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014412:Tumor Virus Infections / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor