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Eur J Immunol. 2015 Dec;45(12):3257-68. doi: 10.1002/eji.201445243. Epub 2015 Oct 19.

The proteasome immunosubunits, PA28 and ER-aminopeptidase 1 protect melanoma cells from efficient MART-126-35 -specific T-cell recognition.

Author information

1
Institut für Biochemie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
2
Institut für Molekulare und Klinische Immunologie, Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany.
3
Klinik für Dermatologie, Universitätsklinikum Essen, Essen and German Cancer Consortium (DKTK), Universität Duisburg-Essen, Essen, Germany.
4
INSERM, Unité 1151, Hôpital Necker, Paris, France.
5
Institut für Anatomie, Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany.
6
DZHK (German Centre for Cardiovascular Research), Institut für Biochemie, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Abstract

The immunodominant MART-1(26(27)-35) epitope, liberated from the differentiation antigen melanoma antigen recognized by T cells/melanoma antigen A (MART-1/Melan-A), has been frequently targeted in melanoma immunotherapy, but with limited clinical success. Previous studies suggested that this is in part due to an insufficient peptide supply and epitope presentation, since proteasomes containing the immunosubunits β5i/LMP7 (LMP, low molecular weight protein) or β1i/LMP2 and β5i/LMP7 interfere with MART-1(26-35) epitope generation in tumor cells. Here, we demonstrate that in addition the IFN-γ-inducible proteasome subunit β2i/MECL-1 (multicatalytic endopeptidase complex-like 1), proteasome activator 28 (PA28), and ER-resident aminopeptidase 1 (ERAP1) impair MART-1(26-35) epitope generation. β2i/MECL-1 and PA28 negatively affect C- and N-terminal cleavage and therefore epitope liberation from the proteasome, whereas ERAP1 destroys the MART-1(26-35) epitope by overtrimming activity. Constitutive expression of PA28 and ERAP1 in melanoma cells indicate that both interfere with MART-1(26-35) epitope generation even in the absence of IFN-γ. In summary, our results provide first evidence that activities of different antigen-processing components contribute to an inefficient MART-1(26-35) epitope presentation, suggesting the tumor cell's proteolytic machinery might have an important impact on the outcome of epitope-specific immunotherapies.

KEYWORDS:

Antigen processing; Cellular cytotoxicity; ER-aminopeptidase; Melanoma; Melanoma antigen recognized by T cells/melanoma antigen A; PA28; Proteasome subunit

PMID:
26399368
DOI:
10.1002/eji.201445243
[Indexed for MEDLINE]
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