Distinct molecular mechanisms leading to deficient expression of ER-resident aminopeptidases in melanoma.
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.
Kamphausen
Esther
E
Institute of Medical Immunology, Martin-Luther-University Halle-Wittenberg, Magdeburger Str. 2, 06112, Halle (Saale), Germany.
Kellert
Christiane
C
Abbas
Tarish
T
Akkad
Nadja
N
Tenzer
Stefan
S
Pawelec
Graham
G
Schild
Hansjoerg
H
van Endert
Peter
P
Seliger
Barbara
B
D020121:5' Untranslated Regions / Q000235:genetics; D000626:Aminopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017951:Antigen Presentation / Q000187:drug effects; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000276:immunology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015778:Minor Histocompatibility Antigens; D016297:Mutagenesis, Site-Directed
D020121:5' Untranslated Regions; D000951:Antigens, Neoplasm; D006680:HLA Antigens; D015778:Minor Histocompatibility Antigens; D007371:Interferon-gamma; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C503944:ERAP2 protein, human