Morphological evidence of an activated cytotoxic T-cell infiltrate in EBV-positive gastric carcinoma preventing lymph node metastases.
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.
van Beek
Josine
J
Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
zur Hausen
Axel
A
Snel
Sander N
SN
Berkhof
Johannes
J
Kranenbarg
Elma Klein
EK
van de Velde
Cornelis J H
CJ
van den Brule
Adriaan J C
AJ
Middeldorp
Jaap M
JM
Meijer
Chris J L M
CJ
Bloemena
Elisabeth
E
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*
D014408:Biomarkers, Tumor