Molecular and pathological features in patients with gastric cancer in Argentina. Association between Epstein Barr Virus, MSI, PD-L1 expression and T-cells infiltration

Abstract

Introduction: The incidence of gastric cancer (CG) in Argentina is about 3900 cases and 3200 deaths per year. In the recent molecular classification stand out among others, those tumors associated with Epstein Barr virus (EBV) infection and microsatellite instability (MSI). Both are associated with an increase in the lymphoid infiltrate and this tumor microenvironment has been related to an increase in the expression of PD-L1. The clinical relevance of these features remains unclear. The objective of this study is to evaluate the expression of EBV and MSI, to analyze the expression of PD-L1 together with the presence of CD3 and CD8 lymphocytes in the tumor microenvironment and to describe their relationship with clinical-pathological characteristics. Methods: We evaluated a cohort of 47 patients with gastric adenocarcinoma, without neoadjuvant treatment, who underwent curative surgery. Immunohistochemistry (IHC) for MLH1, PMS2, MSH2, MSH6, PD-L1, CD3 and CD8; MSI assay with BAT25, BAT26, NR21, NR24, and MONO27 markers, and qualitative detection of EBV were performed. Results: Qualitative PCR for EVB was positive in 21% (n = 10) of cases. MSI was identified in 8% (N = 4) cases. The status of MSI and EBV positive GC were mutually exclusive. Correlation between MSI and MMR deficiency by IHC was 100% (MLH1 and PMS2 loss in all cases). CG EBV positive and CG MSI were more frequent in male patients, older than 50 years and distal gastric localization. The intestinal histological type was the most frequent in CG MSI, whereas represented 50% in CG EBV cases. 50% of the GC EBV and 75% of the CG MSI showed a high density of tumor-infiltrating lymphocytes (TILs). PDL1 was positive in tumor cells and in infiltrating immune cells in 28% (n = 13) cases (6/10 CG-EVB positive, 2/4 CG-MSI and 5/33 CG-EVB negative / MSS). GCs EBV positive and CG MSI that expressed PD-L1 had a high density of CD3 T-lymphocytes in both intratumoral region and invasion margin but low for CD8 T lymphocytes. Conclusion: In our gastric patients, PD-L1 expression was associated with distinct molecular and histopathological features including a high density of CD3 T lymphocytes, MSI status, and EBV. These data could be relevant to identify potential candidate patients for immunotherapies.