Genetic Variants in TAP Are Associated with High-Grade Cervical Neoplasia

Abstract

Purpose The transporter associated with antigen processing (TAP) is essential in assembling MHC-I proteins. Human papillomavirus (HPV) evades immune recognition by decreasing class I MHC cell surface expression through down-regulation of TAP1 levels. Consistent with heterogeneity in MHC expression is the individual variability in clearing detectable HPV infections. Genetic polymorphisms in TAP genes may affect protein structure, function, and the ability to clear HPV infection. Experimental Design Case-control study of women with cervical intraepithelial neoplasia (CIN) II or III (n = 114) and women without high-grade CIN (n = 366). Five nonsynonymous single nucleotide polymorphisms (SNP) in TAP1 and TAP2 were genotyped using DNA collected in cervicovaginal lavage samples using microsphere array technology (Luminex ×MAP). HPV typing was done using a PCR-based system with MY09/MY11 primers. TAP1 and TAP2 SNPs were validated by direct sequencing. Results Differences in allele distribution between women with high-grade cervical neoplasia and women without was seen for TAP1 I333V (P = 0.02) and TAP1 D637G (p = 0.01).The odds ratios (OR) for CIN III were significantly lower among carriers of the TAP1 I333V polymorphism (OR, 0.28; 95% confidence interval, 0.1-0.8), and TAP1 D637G polymorphism (OR, 0.27; 95% confidence interval, 0.1-0.7). These associations remained significant even after restricting the evaluation to women who were positive for high-risk HPV types. Conclusions In addition to the down-regulation of MHC-1 by oncogenic HPV, HPV pathogenesis might be facilitated by polymorphisms in the TAP proteins. Identifying TAP polymorphisms may potentially be used to identify women less susceptible to progression to high-grade CIN and cervical cancer.

Different Expression Levels of the TAP Peptide Transporter Lead to Recognition of Different Antigenic Peptides by Tumor-Specific CTL

“…Indeed, viruses are able to interfere with MHC-I-viral peptide complex formation by inhibiting TAP so as to evade CTL recognition and destruction of infected cells (3)(4)(5)(6)(7)(8)(9)(10). TAP deficiencies have also been observed in a wide variety of human cancers, including cervical carcinoma (11), head and neck carcinoma (12), melanoma and gastric cancer (13)(14)(15), and are associated with tumor escape from immune system control. Therefore, better knowledge of proteasome-TAP processing regulation and the discovery of alternative pathways for tumor Ag degradation may improve antitumor immune responses and immunotherapy approaches.…”

From HPV Infection to Oncogenesis: A Brief Review of the Complex Immunobiological Events

“…There remain many questions about the precise details and kinetics of the various immune processes across the natural history of cervical neoplasia and in particular the reasons why immune control fails in some individuals increasing the likelihood of progression. Immunogenetic factors play some role in susceptibility and/or progression of oncogenic HPV infections [4,72].…”

“…It is clear that the immune system has an important role in controlling HPV infection as is apparent from observations showing that individuals with iatrogenic immunosuppression or primary immunodeficiencies are predisposed to *Address correspondence to this author at the CRUK Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, United Kingdom; Tel: 00441614463127; Fax: 00441614463109; E-mail: pstern@picr.man.ac.uk persistent HPV infection and subsequent carcinoma [3]. Additionally there appear to be genetic polymorphisms of immune function genes that may allow for greater immune protection in some than in others [4][5][6]. While immune function clearly plays a role, other necessary steps must occur before malignant transformation, including intracellular replication and expression of the HPV genome and integration into the host genome.…”

Transcriptional analysis of immune‐related genes in dendritic cells from hepatitis B surface antigen (HBsAg)‐positive transgenic mice and regulation of Fc gamma receptor IIB by HBsAg‐anti‐HBs complex

“…In contrast, genes coding for TAP-1 (transporter-associated antigen processing gene), chemokine ligands, Lime1, and interferon-activated genes (Ifi203 and Mx1) were all down-regulated. TAP-1 protein has been found crucial for the assembly of MHC-I proteins, and human papilloma virus was reported to down-regulate TAP-1 levels by decreasing class I MHC expression, thus evading host immune responses [Einstein et al, 2009]. Lck encodes a plasma membrane-associated lymphocyte-specific protein tyrosine kinase, which is important for the initiation of signaling of the T cell receptor and trafficking of Lck to endosomes and is critical for immunological synapse formation [Gorska et al, 2009].…”