High MHC-II expression in Epstein–Barr virus-associated gastric cancers suggests that tumor cells serve an important role in antigen presentation

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.

The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins

“…The effect is suggested to be a consequence of upregulation of MHC-II expression that is concomitant with the expression of foreign viral antigens. Using RNA-seq data from 400 gastric cancer patients, the upregulation of all MHC-II involved genes, including CIITA and RFX5, was observed compared to normal tissues or other types of gastric cancers [ 137 ]. Expression of these genes was unexpected, as EBV infection induces expression of the viral protein BZLF1 (ZEBRA, Zta), which represses transcription of CIITA [ 111 , 138 ].…”

“…While expression of the viral protein was still found in many of these cancers, upregulation of MHC-II was correlated with higher levels of intratumoral IFNγ. These results suggested an APC function of cancer cells, increasing the immunogenicity of the tumor microenvironment and thus helping cancer elimination [ 137 ].…”

Clinicopathological and Immunomicroenvironment Characteristics of Epstein–Barr Virus-Associated Gastric Cancer in a Chinese Population

“…Expression levels of genes involved in antigen presentation are also significantly upregulated in EBVaGC. The authors also described the significant increase in the expression of co-stimulatory molecules involved in T cell activation and survival in EBVaGC ( 8 ). Compared with non-EBVaGC, EBVaGC patients reportedly exhibit increased mRNA expression profiles of immune-related genes, including increased expression of cytotoxic T cells, Th1 cells and pro-inflammatory factors, as well as Tregs and immune suppression checkpoint gene expression ( 9 ).…”

Overview of Epstein–Barr-Virus-Associated Gastric Cancer Correlated with Prognostic Classification and Development of Therapeutic Options

“…High MHC-II expression in EBVaGCs suggests that this tumor shows a more important role in antigen presentation than EBV-negative GC [ 65 ]. Nonetheless, although, EBVaGC recruits numerous reactive immune cells [ 114 ], specifically CD8+ T cells and macrophages [ 115 ], numerous strategies are used by EBV to evade the immune response. Among the latest discoveries are the production of EBV miRNAs, the use of host-secreted exosomes to transfer immunosuppressive activities to neighboring cells, and the alteration of autophagy and cell metabolism.…”