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01.01.2019 | Original Article

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

verfasst von: Irene Gullo, Patrícia Oliveira, Maria Athelogou, Gilza Gonçalves, Marta L. Pinto, Joana Carvalho, Ana Valente, Hugo Pinheiro, Sara Andrade, Gabriela M. Almeida, Ralf Huss, Kakoli Das, Patrick Tan, José C. Machado, Carla Oliveira, Fátima Carneiro

Erschienen in: Gastric Cancer | Ausgabe 1/2019

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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.

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Titel: New insights into the inflamed tumor immune microenvironment of gastric cancer with lymphoid stroma: from morphology and digital analysis to gene expression
verfasst von: Irene Gullo
Patrícia Oliveira
Maria Athelogou
Gilza Gonçalves
Marta L. Pinto
Joana Carvalho
Ana Valente
Hugo Pinheiro
Sara Andrade
Gabriela M. Almeida
Ralf Huss
Kakoli Das
Patrick Tan
José C. Machado
Carla Oliveira
Fátima Carneiro
Publikationsdatum: 01.01.2019
Verlag: Springer Japan
Erschienen in: Gastric Cancer / Ausgabe 1/2019
Print ISSN: 1436-3291
Elektronische ISSN: 1436-3305
DOI: https://doi.org/10.1007/s10120-018-0836-8

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