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

• Type: Article in International Scientific Journal
• Date: 2019

Authors

Gullo, I (Author) FMUP; Oliveira, P (Author) Other; Athelogou, M (Author) Other; Goncalves, G (Author) Other; Pinto, ML (Author) Other; Carvalho, J (Author) Other; Valente, A (Author) Other; Pinheiro, H (Author) Other; Andrade, S (Author) Other; Almeida, GM (Author) Other; Huss, R (Author) Other; Das, K (Author) Other; Tan, P (Author) Other; Machado JC (Author) FMUP; Oliveira C (Author) FMUP; Carneiro F (Author) FMUP

Journal

Title: Gastric Cancer

Vol. 22

Pages: 77-90

ISSN: 1436-3291

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 26 Citations

Scopus - 26 Citations

Other information

Authenticus ID: P-00Q-30R

DOI: 10.1007/s10120-018-0836-8

Abstract (EN): BackgroundGastric 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.MethodsTwenty-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.ResultsGCLSs 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.ConclusionsThis study shows that GCLS has a distinctive clinico-pathological and molecular profile. Furthermore, through an in-depth study of tumor immune microenvironmentby digital analysis and mRNA expression profilingit highlights the role of EBV infection in promoting an inflamed tumor microenvironment, with putative therapeutic implications.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14