Cancer Immunology, Immunotherapy

, Volume 62, Issue 4, pp 715–726

Imatinib mesylate and nilotinib affect MHC-class I presentation by modulating the proteasomal processing of antigenic peptides

  • Stefanie Andrea Erika Held
  • Katharina Maria Duchardt
  • Stefan Tenzer
  • Thomas Rückrich
  • Karin von Schwarzenberg
  • Anita Bringmann
  • Christian Kurts
  • Hansjörg Schild
  • Christoph Driessen
  • Peter Brossart
  • Annkristin Heine
Original article

DOI: 10.1007/s00262-012-1373-7

Cite this article as:
Held, S.A.E., Duchardt, K.M., Tenzer, S. et al. Cancer Immunol Immunother (2013) 62: 715. doi:10.1007/s00262-012-1373-7

Abstract

Imatinib (IM) has been described to modulate the function of dendritic cells and T lymphocytes and to affect the expression of antigen in CML cells. In our study, we investigated the effect of the tyrosine kinase inhibitors IM and nilotinib (NI) on antigen presentation and processing by analyzing the proteasomal activity in CML cell lines and patient samples. We used a biotinylated active site-directed probe, which covalently binds to the proteasomally active beta-subunits in an activity-dependent fashion. Additionally, we analyzed the cleavage and processing of HLA-A3/11- and HLA-B8-binding peptides derived from BCR-ABL by IM- or NI-treated isolated 20S immunoproteasomes using mass spectrometry. We found that IM treatment leads to a reduction in MHC-class I expression which is in line with the inhibition of proteasomal activity. This process is independent of BCR-ABL or apoptosis induction. In vitro digestion experiments using purified proteasomes showed that generation of epitope-precursor peptides was significantly altered in the presence of NI and IM. Treatment of the immunoproteasome with these compounds resulted in an almost complete reduction in the generation of long precursor peptides for the HLA-A3/A11 and −B8 epitopes while processing of the short peptide sequences increased. Treatment of isolated 20S proteasomes with serine-/threonine- and tyrosine-specific phosphatases induced a significant downregulation of the proteasomal activity further indicating that phosphorylation of the proteasome regulates its function and antigen processing. Our results demonstrate that IM and NI can affect the immunogenicity of malignant cells by modulating proteasomal degradation and the repertoire of processed T cell epitopes.

Keywords

Chronic myeloid leukemiaProteasomeImatinibNilotinibAntigen processing

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Stefanie Andrea Erika Held
    • 1
  • Katharina Maria Duchardt
    • 3
  • Stefan Tenzer
    • 2
  • Thomas Rückrich
    • 3
  • Karin von Schwarzenberg
    • 1
  • Anita Bringmann
    • 1
  • Christian Kurts
    • 6
  • Hansjörg Schild
    • 2
  • Christoph Driessen
    • 4
  • Peter Brossart
    • 1
    • 5
  • Annkristin Heine
    • 1
  1. 1.Department of Hematology and OncologyUniversity Hospital BonnBonnGermany
  2. 2.Institute of ImmunologyUniversity MainzMainzGermany
  3. 3.Department of Hematology, Oncology, Immunology, and PulmonologyUniversity Hospital TübingenTübingenGermany
  4. 4.Department of Oncology and HematologyCantonal Hospital St. GallenSt. GallenSwitzerland
  5. 5.Hämatologie/OnkologieMedizinische Klinik IIIBonnGermany
  6. 6.Institutes of Molecular Medicine and Experimental Immunology (IMMEI)University of BonnBonnGermany