Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 2018-05-19, Vol.22 (1), p.77-90
Gastric cancer with lymphoid stroma (GCLS) is characterized by prominent stromal infiltration of T-lymphocytes. The aim of this study was to investigate GCLS biology through analysis of clinicopathological features, EBV infection, microsatellite instability (MSI), immune gene-expression profiling and PD-L1 status in neoplastic cells and tumor immune microenvironment.
Twenty-four GCLSs were analyzed by RNA in situ hybridization for EBV (EBER), PCR/fragment analysis for MSI, immunohistochemistry (PD-L1, cytokeratin, CD3, CD8), co-immunofluorescence (CK/PD-L1, CD68/PD-L1), NanoString gene-expression assay for immune-related genes and
copy number alterations. CD3+ and CD8+ T-cell densities were calculated by digital analysis. Fifty-four non-GCLSs were used as control group.
GCLSs displayed distinctive clinicopathological features, such as lower pTNM stage (
= 0.02) and better overall survival (
= 0.01). EBV+ or MSI-high phenotype was found in 66.7 and 16.7% cases, respectively. GCLSs harbored a cytotoxic T-cell-inflamed profile, particularly at the invasive front of tumors (
〈 0.01) and in EBV+ cases (
= 0.01). EBV+ GCLSs, when compared to EBV− GCLSs, showed higher mRNA expression of genes related to Th1/cytotoxic and immunosuppressive biomarkers. PD-L1 protein expression, observed in neoplastic and immune stromal cells (33.3 and 91.7%, respectively), and
amplification (18.8%) were restricted to EBV+/MSI-high tumors and correlated with high values of
This study shows that GCLS has a distinctive clinico-pathological and molecular profile. Furthermore, through an in-depth study of tumor immune microenvironment—by digital analysis and mRNA expression profiling—it highlights the role of EBV infection in promoting an inflamed tumor microenvironment, with putative therapeutic implications.
Abdominal Surgery ; Cancer Research ; Epstein–Barr virus (EBV) ; Gastric cancer ; Gastroenterology ; Gastroenterology & Hepatology ; Gene expression profiling ; Life Sciences & Biomedicine ; Medicine ; Medicine & Public Health ; Microsatellite instability (MSI) ; Oncology ; Original Article ; PD-L1 ; Science & Technology ; Surgical Oncology
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