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Distinct molecular mechanisms leading to deficient expression of ER-resident aminopeptidases in melanoma

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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

References

  1. Jensen PE (2007) Recent advances in antigen processing and presentation. Nat Immunol 8:1041–1048

    Article  CAS  PubMed  Google Scholar 

  2. Yewdell JW (2005) The seven dirty little secrets of major histocompatibility complex class I antigen processing. Immunol Rev 207:8–18

    Article  CAS  PubMed  Google Scholar 

  3. Hammer GE, Kanaseki T, Shastri N (2007) The final touches make perfect the peptide-MHC class I repertoire. Immunity 26:397–406

    Article  CAS  PubMed  Google Scholar 

  4. Goldberg AL, Cascio P, Saric T, Rock KL (2002) The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides. Mol Immunol 39:147–164

    Article  CAS  PubMed  Google Scholar 

  5. Saveanu L, Carroll O, Hassainya Y, van Endert P (2005) Complexity, contradictions, and conundrums: studying post-proteasomal proteolysis in HLA class I antigen presentation. Immunol Rev 207:42–59

    Article  CAS  PubMed  Google Scholar 

  6. Levy F, Burri L, Morel S et al (2002) The final N-terminal trimming of a subaminoterminal proline-containing HLA class I-restricted antigenic peptide in the cytosol is mediated by two peptidases. J Immunol 169:4161–4171

    CAS  PubMed  Google Scholar 

  7. Endert P (2008) Role of tripeptidyl peptidase II in MHC class I antigen processing—the end of controversies. Eur J Immunol 38:609–613

    Article  PubMed  Google Scholar 

  8. Rock KL, York IA, Goldberg AL (2004) Post-proteasomal antigen processing for major histocompatibility complex class I presentation. Nat Immunol 5:670–677

    Article  CAS  PubMed  Google Scholar 

  9. Stoltze L, Schirle M, Schwarz G et al (2000) Two new proteases in the MHC class I processing pathway. Nat Immunol 5:413–418

    Article  Google Scholar 

  10. Hammer GE, Gonzalez F, James E, Nolla H, Shastri N (2007) In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides. Nat Immunol 8:101–108

    Article  CAS  PubMed  Google Scholar 

  11. Chang SC, Momburg F, Bhutani N, Goldberg AL (2006) The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc Natl Acad Sci USA 102:17107–17112

    Article  Google Scholar 

  12. Hammer GE, Gonzalez F, Champsaur M, Cado D, Shastri N (2006) The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules. Nat Immunol 7:103–112

    Article  CAS  PubMed  Google Scholar 

  13. Dunn GP, Koebel CM, Schreiber RD (2006) Interferons, immunity and cancer immunoediting. Nat Rev Immunol 6:836–848

    Article  CAS  PubMed  Google Scholar 

  14. Cabrera T, Maleno I, Collado A, Lopez Nevot MA, Tait BD, Garrido F (2007) Analysis of HLA class I alterations in tumors: choosing a strategy based on known patterns of underlying molecular mechanisms. Tissue Antigens 69 Suppl 1:264–268

    Article  CAS  PubMed  Google Scholar 

  15. Seliger B, Ritz U, Ferrone S (2006) Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation. Int J Cancer 118:129–138

    Article  CAS  PubMed  Google Scholar 

  16. Chang CC, Ferrone S (2007) Immune selective pressure and HLA class I antigen defects in malignant lesions. Cancer Immunol Immunother 56:227–236

    Article  CAS  PubMed  Google Scholar 

  17. Mehta AM, Jordanova ES, Kenter GG, Ferrone S, Fleuren GJ (2008) Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma. Cancer Immunol Immunother 57:197–206

    Article  CAS  PubMed  Google Scholar 

  18. Fruci D, Giacomini P, Nicotra MR et al (2008) Altered expression of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in transformed non-lymphoid human tissues. J Cell Physiol 216:742–749

    Article  CAS  PubMed  Google Scholar 

  19. Fruci D, Ferracuti S, Limongi MZ et al (2006) Expression of endoplasmic reticulum aminopeptidases in EBV-B cell lines from healthy donors and in leukemia/lymphoma, carcinoma, and melanoma cell lines. J Immunol 176:4869–4879

    CAS  PubMed  Google Scholar 

  20. Varona A, Blanco L, Lopez JI et al (2007) Altered levels of acid, basic, and neutral peptidase activity and expression in human clear cell renal cell carcinoma. Am J Physiol Renal Physiol 292:F780–F788

    Article  CAS  PubMed  Google Scholar 

  21. Mehta AM, Jordanova ES, van Wezel T et al (2007) Genetic variation of antigen processing machinery components and association with cervical carcinoma. Genes Chromosomes Cancer 46:577–586

    Article  CAS  PubMed  Google Scholar 

  22. Schatz MM, Peters B, Akkad N et al (2008) Characterizing the N-terminal processing motif of MHC class I ligands. J Immunol 180:3210–3217

    CAS  PubMed  Google Scholar 

  23. Reits E, Neijssen J, Herberts C et al (2004) A major role for TPPII in trimming proteasomal degradation products for MHC class I antigen presentation. Immunity 20:495–506

    Article  CAS  PubMed  Google Scholar 

  24. Cui X, Rouhani FN, Hawari F, Levine SJ (2003) Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding. J Immunol 171:6814–6819

    CAS  PubMed  Google Scholar 

  25. Akada T, Yamazaki T, Miyashita H et al (2002) Puromycin insensitive leucyl-specific aminopeptidase (PILSAP) is involved in the activation of endothelial integrins. J Cell Physiol 193:253–262

    Article  CAS  PubMed  Google Scholar 

  26. Shido F, Ito T, Nomura S et al (2006) Endoplasmic reticulum aminopeptidase-1 mediates leukemia inhibitory factor-induced cell surface human leukocyte antigen-G expression in JEG-3 choriocarcinoma cells. Endocrinology 147:1780–1788

    Article  CAS  PubMed  Google Scholar 

  27. Mehta AM, Jordanova ES, Corver WE et al (2009) Single nucleotide polymorphisms in antigen processing machinery component ERAP1 significantly associate with clinical outcome in cervical carcinoma. Genes Chromosomes Cancer 48:410–418

    Article  CAS  PubMed  Google Scholar 

  28. Jung D, Hilmes C, Knuth A, Jaeger E, Huber C, Seliger B (1999) Gene transfer of the co-stimulatory molecules B7–1 and B7–2 enhances the immunogenicity of human renal cell carcinoma to a different extent. Scand J Immunol 50:242–249

    Article  CAS  PubMed  Google Scholar 

  29. Herrmann F, Trowsdale J, Huber C, Seliger B (2003) Cloning and functional analyses of the mouse tapasin promoter. Immunogenetics 55:379–388

    Article  CAS  PubMed  Google Scholar 

  30. Atkins D, Ferrone S, Schmahl GE, Storkel S, Seliger B (2004) Downregulation of HLA class I antigen processing molecules: an immune escape mechanism of renal cell carcinoma. J Urol 171:885–889

    Article  CAS  PubMed  Google Scholar 

  31. Seliger B, Ritz U, Abele R, Bock M, Tampé R, Sutter G, Drexler I et al (2001) Immune escape of melanoma: first evidence of structural alterations in two distinct components of the MHC class I antigen processing pathway. Cancer Res 61:8647–8650

    CAS  PubMed  Google Scholar 

  32. Kanaseki T, Blanchard N, Hammer GE, Gonzalez F, Shastri N (2006) ERAAP synergizes with MHC class I molecules to make the final cut in the antigenic peptide precursors in the endoplasmic reticulium. Immunity 25:795–806

    Article  CAS  PubMed  Google Scholar 

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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

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  1. Esther Kamphausen
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  2. Christiane Kellert
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  3. Tarish Abbas
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  4. Nadja Akkad
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  7. Hansjoerg Schild
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  8. Peter van Endert
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  9. Barbara Seliger
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Correspondence to Barbara 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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  • DOI: https://doi.org/10.1007/s00262-010-0856-7

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