Identification of microRNAs Targeting the Transporter Associated with Antigen Processing TAP1 in Melanoma.

Maria-Filothei Lazaridou,Peter Koelblinger,Barbara Seliger,Michael Friedrich,Karthikeyan Subbarayan,Sandy Tretbar,Reinhard Dummer,Chiara Massa,Anja Mueller,Diana Handke

doi:10.3390/jcm9092690

Abstract

The underlying molecular mechanisms of the aberrant expression of components of the HLA class I antigen processing and presentation machinery (APM) in tumors leading to evasion from T cell-mediated immune surveillance could be due to posttranscriptional regulation mediated by microRNAs (miRs). So far, some miRs controlling the expression of different APM components have been identified. Using in silico analysis and an miR enrichment protocol in combination with small RNA sequencing, miR-26b-5p and miR-21-3p were postulated to target the 3′ untranslated region (UTR) of the peptide transporter TAP1, which was confirmed by high free binding energy and dual luciferase reporter assays. Overexpression of miR-26b-5p and miR-21-3p in melanoma cells downregulated the TAP1 protein and reduced expression of HLA class I cell surface antigens, which could be reverted by miR inhibitors. Moreover, miR-26b-5p overexpression induced a decreased T cell recognition. Furthermore, an inverse expression of miR-26b-5p and miR-21-3p with TAP1 was found in primary melanoma lesions, which was linked with the frequency of CD8+ T cell infiltration. Thus, miR-26-5p and miR-21-3p are involved in the HLA class I-mediated immune escape and might be used as biomarkers or therapeutic targets for HLA class Ilow melanoma cells.

Highlights

Human solid tumors including melanoma develop different strategies to escape T cell-mediated immune surveillance such as loss or downregulation of human leukocyte antigens (HLA) class I molecules
The posttranscriptional regulation of HLA class I APM components has come into focus, which could be mediated by RNA binding proteins (RBP) or small non-coding microRNAs [13,14,15,16]
Using the “starbase” web tool and several available datasets including the “The Cancer Genome Atlas (TCGA) Skin Cutaneous Melanoma (SKCM)” dataset [70,81], the correlation between the expression of TAP1 and HLA class I loci was re-evaluated in order to determine the prognostic relevance of TAP1 (Table 1a), HLA-A (Table 1b), HLA-B (Table 1c) and HLA-C (Table 1d) expression patterns in different cancer types including skin cutaneous melanoma

Summary

Introduction

Human solid tumors including melanoma develop different strategies to escape T cell-mediated immune surveillance such as loss or downregulation of human leukocyte antigens (HLA) class I molecules. This is frequently due to defects in the expression of various components of the antigen processing and presentation machinery (APM), which can be associated with disease progression and reduced patient survival [1,2,3,4]. The deregulation of HLA class I APM components in tumors could occur at the transcriptional, epigenetic, posttranscriptional and/or posttranslational level and depend on the tumor type analyzed [2,10,11,12]. The posttranscriptional regulation of HLA class I APM components has come into focus, which could be mediated by RNA binding proteins (RBP) or small non-coding microRNAs (miRs) [13,14,15,16]

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Conclusion