Downregulation of expression of transporters associated with antigen processing 1 and 2 and human leukocyte antigen I and its effect on immunity in nasopharyngeal carcinoma patients

Abstract

Abstract. The human leukocyte antigen (HLA)-I and antigen-processing machinery (APM) are crucial in the anticancer immune response. The aim of this study was to assess the clinical significance of the APM components [transporters associated with antigen processing (TAP)-1 and -2 and HLA-I] in nasopharyngeal carcinoma (NPC). A total of 58 NPC specimens and 20 healthy specimens used as control were evaluated by semiquantitative immunohistochemistry for three APM components (TAP-1, TAP-2 and HLA-I). The expression of the APM components in NPC was downregulated. CD4 + and CD8 + T cells were measured by flow cytometry and IL-10 was measured by ELISA. The number of CD8 + T cells and the expression of IL-10 were higher and the number of CD4 + T cells was lower in NPC, compared to the controls. The number of CD8 + T cells and the expression of IL-10 were negatively correlated with TAP-1, TAP-2 and HLA-I expression. The clinical phase, lymph node metastasis, distant metastasis, pathological type, TAP-1 expression, TAP-2 expression and HLA-I expression were identified as prognostic factors by the Kaplan-Meier analysis. A multivariate analysis using a Cox regression model indicated that distant metastasis and the downregulation of HLA-Ⅰ expression were independent unfavorable prognostic factors. In conclusion, the lower expression of HLA-I induced immunosuppression in NPC patients and was associated with a poor prognosis. IntroductionViruses and tumors evade cytotoxic T lymphocyte-mediated host immunity through the downregulation of antigen-presentation machineries. This may be achieved by either the downregulation of transcription of antigen presentation genes, or the post-translational inactivation of the proteins involved in antigen presentation (1). The optimal cell surface expression of human leukocyte antigen (HLA) molecules requires the coordinated expression of several genes, such as transporters associated with antigen processing (TAP)-1 and -2, low molecular weight peptide (LMP)-2 and -7 and tapasin, as well as HLA class I heavy chain and β 2 -microglobulin (β 2 M). In cases of concurrent tumorigenesis and viral infection, the expression of these genes and the function of the encoded proteins are often impaired.Latent Epstein-Barr virus (EBV) infections are associated with lymphocyte and epithelial cell malignancies, with nasopharyngeal carcinoma (NPC) being the most frequent EBV-associated malignancy (2). The EBV-associated, undifferentiated form of NPC exhibits the most consistent association with EBV worldwide and is particularly common in China and Southeast Asia, reaching a peak incidence of ~20-30 cases per 100,000 individuals (3). In addition to genetic predisposition, EBV infection and environmental factors, such as dietary and geographic components, were considered to be important in the aetiology of NPC (4-6). Previous studies that used quantitative polymerase chain reaction to measure circulating tumor-derived EBV DNA in the blood of NPC patients demonstrated that the level of pre-treatment EBV DNA was...

The Global Landscape of EBV-Associated Tumors

“…These findings, bolstered by the observation that A * 0201 and A * 1101 mediate the strongest responses to CD8+ T cell epitopes in LMP2, suggest that virus-specific CD8+ T cell surveillance does play a protective role at some stage in the pathogenesis of these tumors (23). This is further supported by the fact that in up to 30% cases both EBV-positive HL (177) and NPC (178) appear to have either partially or completely lost HLA I expression, a finding which for NPC has recently been validated by genomic studies showing mutation of either individual HLA I alleles or pan-HLA pathway genes (142). Parallel studies that focus on the EBV-positive subset of gastric cancers are awaited with interest.…”

The Microenvironment in Epstein–Barr Virus-Associated Malignancies

“…There is less data on NPC, but it has been reported that complete loss of HLA class I expression occurs in approximately 20% of cases and partial loss in an additional 58% of cases [ 98 ]. Another study showed a loss of HLA class I expression in 50% of NPC cases [ 99 ]. Other changes in the antigen presenting machinery may alter the quality and quantity of presented peptides as well.…”

EBNA2 driven enhancer switching at the CIITA-DEXI locus suppresses HLA class II gene expression during EBV infection of B-lymphocytes

“…HLA-II is up regulated in EBVaGC, where EBNA2 is not typically expressed [69]. This is also different than the effects observed in an EBV+ nasopharyngeal carcinoma, where HLA class II expression is down iñ 50% of the cases [70,71]. Thus, EBNA2 down regulation of CIITA may be cell-type specific, depending on chromatin domain structure and enhancer wiring particular to B-cells but perhaps different in EBV epithelial cancers.…”