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Updated: Jun 13, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Distinct molecular mechanisms leading to deficient expression of ER-resident aminopeptidases in melanoma
Esther Kamphausen1, Christiane Kellert, Tarish Abbas
1Institute of Medical Immunology, Martin-Luther-University Halle-Wittenberg, Magdeburger Str. 2, 06112, Halle (Saale), Germany.
Abstract:
Immune surveillance of tumour cells by CD8(+) cytotoxic T cells plays a key role in the establishment and control of an anti-tumour response. This process requires the generation of antigenic peptides, which are largely produced by the proteasome in combination with other proteases located in either the cytoplasm and/or the endoplasmic reticulum (ER). The ER-resident aminopeptidases ERAP1 and ERAP2 trim or even destroy HLA class I-binding peptides thereby shaping the peptide repertoire presented for T cell recognition. So far there exists limited information about the expression pattern of ERAP1 and/or ERAP2 in human tumours of distinct histotypes. Therefore, the expression profiles and modes of regulation of both aminopeptidases were determined in a large series of melanoma cell lines. A heterogeneous expression ranging from high to reduced or even total loss of ERAP1 and/or ERAP2 mRNA and/or protein expression was detected, which often could be induced/upregulated by interferon-gamma treatment. The observed altered ERAP1 and/or ERAP2 expression and activity levels were either mediated by sequence alterations affecting the promoter or enzymatic activities, leading to either transcriptional and/or post-transcriptional downregulation mechanisms or limited or excessive processing activities, which both might have an impact on the antigenic peptide repertoire presented on HLA class I molecules.
Insights
Tumour immune surveillance relies on CD8(+) T cells and antigenic peptides generated by proteasomes and ERAP1/ERAP2 aminopeptidases. This study reveals heterogeneous ERAP1/ERAP2 expression in melanoma, impacting T cell recognition.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- CD8(+) cytotoxic T cells are crucial for anti-tumour immunity.
- Antigenic peptides for T cell recognition are processed by proteasomes and ER-resident aminopeptidases (ERAP1, ERAP2).
- ERAP1 and ERAP2 shape the peptide repertoire presented by HLA class I molecules.
Purpose of the Study:
- To investigate the expression profiles and regulatory mechanisms of ERAP1 and ERAP2 in human melanoma.
- To understand how ERAP1/ERAP2 alterations affect the antigenic peptide repertoire in melanoma.
Main Methods:
- Analysis of ERAP1 and ERAP2 mRNA and protein expression in a large series of melanoma cell lines.
- Assessment of interferon-gamma-induced regulation of ERAP1/ERAP2.
- Investigation of sequence alterations impacting promoter activity and enzymatic function.
Main Results:
- Melanoma cell lines exhibited heterogeneous ERAP1/ERAP2 expression, including reduced or lost expression.
- Interferon-gamma treatment often induced or upregulated ERAP1/ERAP2 expression.
- Altered expression was linked to promoter alterations, transcriptional/post-transcriptional downregulation, or modified processing activities.
Conclusions:
- ERAP1 and ERAP2 expression is highly variable in melanoma, potentially affecting anti-tumour immune responses.
- These alterations can be mediated by genetic and regulatory mechanisms impacting peptide processing.
- Understanding ERAP1/ERAP2 regulation in melanoma is critical for predicting T cell recognition and therapeutic strategies.
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