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. 2019 Jan;22(1):77-90.
doi: 10.1007/s10120-018-0836-8. Epub 2018 May 19.

New insights into the inflamed tumor immune microenvironment of gastric cancer with lymphoid stroma: from morphology and digital analysis to gene expression

Irene Gullo  1   2   3   4 , Patrícia Oliveira  3   4 , Maria Athelogou  5 , Gilza Gonçalves  2   3   4   6 , Marta L Pinto  4   7   8 , Joana Carvalho  3   4 , Ana Valente  3   4 , Hugo Pinheiro  3   4   9 , Sara Andrade  3   4   10 , Gabriela M Almeida  3   4 , Ralf Huss  5 , Kakoli Das  11 , Patrick Tan  11   12   13 , José C Machado  2   3   4 , Carla Oliveira  14   15   16 , Fátima Carneiro  17   18   19   20
Affiliations

New insights into the inflamed tumor immune microenvironment of gastric cancer with lymphoid stroma: from morphology and digital analysis to gene expression

Irene Gullo et al. Gastric Cancer. 2019 Jan.

Abstract

Background: 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.

Methods: 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 PD-L1 copy number alterations. CD3+ and CD8+ T-cell densities were calculated by digital analysis. Fifty-four non-GCLSs were used as control group.

Results: GCLSs displayed distinctive clinicopathological features, such as lower pTNM stage (p = 0.02) and better overall survival (p = 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 (p < 0.01) and in EBV+ cases (p = 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 PD-L1 amplification (18.8%) were restricted to EBV+/MSI-high tumors and correlated with high values of PD-L1 mRNA expression.

Conclusions: 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.

Keywords: Epstein–Barr virus (EBV); Gastric cancer; Gene expression profiling; Microsatellite instability (MSI); PD-L1.

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