Abstract
EBV-associated gastric adenocarcinomas (EBVaGCs) often exhibit better clinical outcomes than EBV negative gastric cancers (GCs), which could be related to their consistent expression of foreign viral antigens. Antigen-presenting cells (APCs) present peptide antigens in the context of the class-II major histocompatibility complex (MHC-II). During inflammatory conditions, epithelial cells express MHC-II and function as accessory APCs. Utilizing RNA-seq data from nearly 400 GC patients, we determined the impact of EBV-status on expression of MHC-II components, genes involved in their regulation, and T-cell co-stimulation. Virtually all MHC-II genes were significantly upregulated in EBVaGCs compared to normal tissues, or other GC subtypes. Genes involved in antigen presentation were also significantly upregulated in EBVaGCs, as were the key MHC-II transcriptional regulators CIITA and RFX5. This was unexpected as the EBV encoded BZLF1 protein can repress CIITA transcription and is expressed in many EBVaGCs. Furthermore, MHC-II upregulation was strongly correlated with elevated intratumoral levels of interferon-gamma. In addition, expression of co-stimulatory molecules involved in T-cell activation and survival was also significantly increased in EBVaGCs. Thus, gastric adenocarcinoma cells may functionally contribute to the highly immunogenic tumor microenvironment observed in EBVaGCs via a previously unappreciated role in interferon-induced antigen presentation.
Highlights
Epstein–Barr virus (EBV)-associated gastric adenocarcinomas (EBVaGCs) often exhibit better clinical outcomes than EBV negative gastric cancers (GCs), which could be related to their consistent expression of foreign viral antigens
EBV-associated gastric adenocarcinomas (EBVaGCs) exhibited significantly upregulated levels of T-cell co-stimulatory genes encoding factors involved in T-cell activation and survival compared to other GC subtypes and normal control tissue. These results indicate that gastric adenocarcinoma cells likely contribute to the highly immunogenic tumor microenvironment observed in EBVaGCs by playing a previously unappreciated role in interferon-induced major histocompatibility complex (MHC-II) dependent antigen presentation
All three of these MHC-II protein complexes have been detected in GC tumor cells by immunohistochemical analyses[40], and their expression is correlated with improved prognosis
Summary
EBV-associated gastric adenocarcinomas (EBVaGCs) often exhibit better clinical outcomes than EBV negative gastric cancers (GCs), which could be related to their consistent expression of foreign viral antigens. Genes involved in antigen presentation were significantly upregulated in EBVaGCs, as were the key MHC-II transcriptional regulators CIITA and RFX5 This was unexpected as the EBV encoded BZLF1 protein can repress CIITA transcription and is expressed in many EBVaGCs. MHC-II upregulation was strongly correlated with elevated intratumoral levels of interferon-gamma. MRNAs for a subset of EBV lytic genes, as well as many viral miRNAs are frequently detected in E BVaGCs10,12,13 These transcripts are unlikely to represent contaminants from lytically infected B-cells infiltrating the tumor, as the lytic BZLF1 protein was detected immunohistochemically in EBVaGC cancer cells[14] and the absolute score for immune cell infiltration was not significantly different between EBV-positive and EBV-negative GC s amples[9]. EBV encoded miRNAs inhibit anti-viral CD4+ and CD8+ T-cell responses during primary infection of B-cells, which could occur in EBV-associated c ancers[17]
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