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. 2020 Feb 21;9(2):499.
doi: 10.3390/cells9020499.

High Levels of Class I Major Histocompatibility Complex mRNA Are Present in Epstein-Barr Virus-Associated Gastric Adenocarcinomas

Farhad Ghasemi  1 , Steven F Gameiro  2 , Tanner M Tessier  2 , Allison H Maciver  3 , Joe S Mymryk  4   5
Affiliations

High Levels of Class I Major Histocompatibility Complex mRNA Are Present in Epstein-Barr Virus-Associated Gastric Adenocarcinomas

Farhad Ghasemi et al. Cells. .

Abstract

Epstein-Barr virus (EBV) is responsible for approximately 9% of stomach adenocarcinomas. EBV-encoded microRNAs have been reported as reducing the function of the class I major histocompatibility complex (MHC-I) antigen presentation apparatus, which could allow infected cells to evade adaptive immune responses. Using data from nearly 400 human gastric carcinomas (GCs), we assessed the impact of EBV on MHC-I heavy and light chain mRNA levels, as well as multiple other components essential for antigen processing and presentation. Unexpectedly, mRNA levels of these genes were as high, or higher, in EBV-associated gastric carcinomas (EBVaGCs) compared to normal control tissues or other GC subtypes. This coordinated upregulation could have been a consequence of the higher intratumoral levels of interferon γ in EBVaGCs, which correlated with signatures of increased infiltration by T and natural killer (NK) cells. These results indicate that EBV-encoded products do not effectively reduce mRNA levels of the MHC-I antigen presentation apparatus in human GCs.

Keywords: EBV; EBVaGC; Epstein–Barr virus; MHC-I; TCGA; antigen presentation; immune evasion; major histocompatibility complex; stomach adenocarcinoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Expression of classical MHC-I heavy chain gene mRNA in gastric carcinoma subtypes and normal gastric tissue. RNA-Sequencing by Expectation Maximization (RSEM) normalized data for the HLA-A (A), HLA-B (B) and HLA-C (C) MHC-I heavy chain genes were extracted from The Cancer Genome Atlas (TCGA) database for the TCGA/PanCancer Atlas gastric/stomach adenocarcinoma (STAD) cohort for EBV-associated gastric carcinomas (EBVaGCs), normal control tissues, and three other gastric cancer (GC) subtypes. False discovery rate (FDR)-adjusted p-values for each statistical comparison are shown on the right for each gene panel. CIN: chromosomal instability; GS: genomically stable; MSI: microsatellite instability.
Figure 2
Figure 2
Expression of non-classical MHC-I heavy chain genes and light chain in gastric carcinoma subtypes and normal gastric tissue. Normalized RNA-seq data for the HLA-E (A), HLA-F (B) and HLA-G (C) MHC-I heavy chain and B2M (D) light chain genes were extracted from the TCGA database for the STAD cohort for EBVaGCs, normal control tissues, and three other GC subtypes. FDR-adjusted p-values for each statistical comparison are shown on the right for each gene panel.
Figure 3
Figure 3
Expression levels of the TAP genes involved in MHC-I-dependent antigen presentation in gastric carcinoma subtypes and normal gastric tissue. Normalized RNA-seq data for the TAP1 (A), TAP2 (B) and TAPBP (C) genes involved in MHC-I-dependent antigen presentation were extracted from the TCGA database for the STAD cohort for EBVaGCs, normal control tissues, and three other GC subtypes. FDR-adjusted p-values for each statistical comparison are shown on the right for each gene panel.
Figure 4
Figure 4
Expression levels of other genes involved in MHC-I-dependent antigen loading in gastric carcinoma subtypes and normal gastric tissue. Normalized RNA-seq data for the CANX (A), CALR (B), PDIA3 (C), ERAP1 (D) and ERAP2 (E) genes involved in MHC-I-dependent antigen presentation were extracted from the TCGA database for the STAD cohort for EBVaGCs, normal control tissues, and three other GC subtypes. FDR-adjusted p-values for each statistical comparison are shown on the right for each gene panel.
Figure 5
Figure 5
Detection of tumor infiltrating T cells and natural killer (NK) cells in gastric carcinoma subtypes and normal gastric tissue. Normalized RNA-seq data for genes indicative of tumor infiltrating T cells including CD3D (A), CD3E (B), and CD3G (C), or FCGR3A (D) for NK cells were extracted from the TCGA database for the STAD cohort for EBVaGCs, normal control tissues, and three other GC subtypes. FDR-adjusted p-values for each statistical comparison are shown on the right for each gene panel.
Figure 6
Figure 6
Expression of mRNA encoding IFN-γ and transcription factors involved in regulating the interferon-dependent activation of MHC-I-dependent antigen presentation and loading genes. Normalized RNA-seq data for the IFN-γ (IFNG) gene (A) and the genes encoding the nucleotide-binding oligomerization domain (NOD)-like receptor caspase recruitment domain containing protein 5 (NLRC5)/MHC-I transactivator (CITA; panel (B)) and Regulatory Factor X5 (RFX5; panel (C)) transcription factors involved in interferon-induced activation of expression of genes involved in MHC-I-dependent antigen presentation were extracted from the TCGA database for the STAD cohort for EBVaGCs, normal control tissues, and three other GC subtypes. FDR-adjusted p-values for each statistical comparison are shown on the right for each gene panel.
Figure 7
Figure 7
Correlation matrix of selected genes involved in the MHC-I antigen presentation pathway. Heatmap of Spearman correlation analysis of mRNA expression of the indicated MHC-I pathway genes in EBVaGC (A). Comparisons with EBV genes reported to antagonize interferon-γ response are also shown. For comparison, Spearman correlations between mRNA levels for interferon-γ (IFNG) and MHC-I pathway genes are also shown for the CIN (B), GS (C), and MSI (D) subtypes. RSEM normalized RNA-seq data for the genes listed above were extracted from the TCGA database for the STAD cohort for EBVaGCs. Pairwise spearman correlations were performed. Numbers in boxes indicate Spearman’s rank correlation coefficient of analyzed gene pairs and p-values.
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References

    1. Yan N., Chen Z.J. Intrinsic antiviral immunity. Nat. Immunol. 2012;13:214–222. doi: 10.1038/ni.2229. - DOI - PMC - PubMed
    1. Takeuchi O., Akira S. Innate immunity to virus infection. Immunol. Rev. 2009;227:75–86. doi: 10.1111/j.1600-065X.2008.00737.x. - DOI - PMC - PubMed
    1. Tscharke D.C., Croft N.P., Doherty P.C., La Gruta N.L. Sizing up the key determinants of the CD8(+) T cell response. Nat. Rev. Immunol. 2015;15:705–716. doi: 10.1038/nri3905. - DOI - PubMed
    1. Hansen T.H., Bouvier M. MHC class I antigen presentation: Learning from viral evasion strategies. Nat. Rev. Immunol. 2009;9:503–513. doi: 10.1038/nri2575. - DOI - PubMed
    1. Epstein M.A., Achong B.G., Barr Y.M. Virus Particles in Cultured Lymphoblasts from Burkitt’s Lymphoma. Lancet. 1964;1:702–703. doi: 10.1016/S0140-6736(64)91524-7. - DOI - PubMed

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