Abstract 2517: Characterization of the immune microenvironment of Epstein-Barr virus associated gastric cancer
Authors: Torres Keila E. , Hill Charlotte N. , Rocha Dario , Fernández Elmer , Wichmann Ignacio A. , Owen Gareth I. , Corvalan Alejandro H. 
Published: June 2022

Abstract
Consistent with better clinical outcome, Epstein-Barr Virus associated gastric cancer (EBVaGC) displays a particular expression pattern of immunological genes and is highly infiltrated by effector immune cells. To decipher potential mechanisms linking tumor infiltrating lymphocytes (TILs) with an expression of immune-related genes in EBVaGC we utilized RNAseq gene expression data from The Cancer Genome Atlas (TCGA) Stomach Adenocarcinoma (STAD) dataset and performed cellular deconvolution analyses by a mixed approach including two complementary approaches (MIXTURE and xCell). In accordance with previous studies, we observed an increase in CD8+ cells and Interferon activity. Further analysis by gene set variation analysis (GSVA) showed an increased exhausted CD8+ signature accompanied by a higher intratumoral Treg signature. Accordingly, an enrichment in both stimulatory and inhibitory immune checkpoint levels on EBVaGC tumors was observed. We next performed differential expression analysis comparing EBVaGC to other STAD subtypes (CIN, GS, HM-SNV, HM-indel) individually. As a result, from this approach, we generated a list of unique EBVaGC-specific genes that was used to construct EBVaGC-specific cell-cell interaction networks. To infer cell-cell interactions underlying the specific tumor immune microenvironment, we implemented the NicheNetR algorithm by including only differentially expressed ligands and targets from the list of EBVaGC genes obtaining a ligand-interaction matrix from which we constructed a EBVaGC-like gene signature. Functional annotation of this ligand-target network showed ligands and targets principally involved in chemotaxis, T-cell apoptosis, and cellular responses to bacterial infection. This signature correlated with better survival not only in EBVaGC but also in other TCGA cohorts such as colon adenocarcinoma and kidney renal clear cell carcinoma. Our findings identified an increase in exhausted CD8+ signature, high intratumoral Treg signature and enrichment in inhibitory immune checkpoint transcripts. We herein propose a new EBVaGC-like gene expression signature that correlates with better survival in multiple cancer types. In-vitro and in-vivo assays will be required for functional validation of these findings as well as clinical trials to confirm the role of our novel EBVaGC-like gene signature in a precision oncology setting. Grant Support: ANID/FONDECYT/POSTDOCTORADO/3201028, CONICYT-FONDAP 15130011, FONDECYT 1191928 & 1180241, IMII P09/016-F, CONICET and Universidad Católica de Córdoba 80020180100029CC, grant 33620180100993CB from the Universidad Nacional de Córdoba.
Citation Format: Keila E. Torres, Charlotte N. Hill, Dario Rocha, Elmer Fernández, Ignacio A. Wichmann, Gareth I. Owen, Alejandro H. Corvalan. Characterization of the immune microenvironment of Epstein-Barr virus associated gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2517.