Distinct molecular mechanisms leading to deficient expression of ER-resident aminopeptidases in melanoma (original) (raw)

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-γ 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.

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Abbreviations

AMC:

7-amino-4-methyl coumarin

APM:

Antigen processing machinery

BLH:

Bleomycin hydrolase

crt:

Calreticulin

ERAP:

ER aminopeptidase associated with antigen processing

gal:

Galactosidase

HC:

Heavy chain

IRF:

Interferon-regulated factor

LAP:

Leucine aminopeptidase

LMP:

Low molecular weight proteins

mut:

Mutant

neoR :

Neomycin resistance

PSA:

Puromycin-sensitive aminopeptidase

RCC:

Renal cell carcinoma

SNP:

Signal nucleotide polymorphism

TFB:

Transcription factor binding site

TPP II:

Tripeptidyl peptidase II

UTR:

Untranslated region

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Acknowledgments

We would like to thank Juergen Bukur and Chiara Massa for fruitful discussions and Claudia Stoerr and Sylvi Magdeburg for excellent secretarial help. Furthermore the authors thank Dr. Markus Meissner for providing us with cell pellets of primary melanocytes. This work is supported by the Deutsche Forschungsgemeinschaft grant DFG SE 581/9-2 (B-S) and the Sonderforschungsbereich SFB490, TP E6 and (H.S.) Z3.

Conflict of interest statement

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Institute of Medical Immunology, Martin-Luther-University Halle-Wittenberg, Magdeburger Str. 2, 06112, Halle (Saale), Germany
    Esther Kamphausen, Christiane Kellert, Tarish Abbas & Barbara Seliger
  2. Institute of Immunology, Johannes Gutenberg University, Obere Zahlbacherstraße 67, 55131, Mainz, Germany
    Nadja Akkad, Stefan Tenzer & Hansjoerg Schild
  3. Section for Transplantation Immunology and Immunohaematology, 2nd Department of Internal Medicine, University of Tuebingen, Waldhoernlestr. 22, 72072, Tübingen, Germany
    Graham Pawelec
  4. INSERM, unité 580, 75015, Paris, France
    Peter van Endert
  5. Faculté de Médicine René Descartes, Université Paris Descartes, 75015, Paris, France
    Peter van Endert

Authors

  1. Esther Kamphausen
  2. Christiane Kellert
  3. Tarish Abbas
  4. Nadja Akkad
  5. Stefan Tenzer
  6. Graham Pawelec
  7. Hansjoerg Schild
  8. Peter van Endert
  9. Barbara Seliger

Corresponding author

Correspondence toBarbara Seliger.

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Kamphausen, E., Kellert, C., Abbas, T. et al. Distinct molecular mechanisms leading to deficient expression of ER-resident aminopeptidases in melanoma.Cancer Immunol Immunother 59, 1273–1284 (2010). https://doi.org/10.1007/s00262-010-0856-7

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