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High frequency of functionally active Melan-a-specific T cells in a patient with progressive immunoproteasome-deficient melanoma.

Cancer Research
American Association for Cancer Research
Publication Date
DOI: 10.1158/0008-5472.can-04-1341
  • Antigens
  • Neoplasm
  • Cysteine Endopeptidases/Deficiency
  • Cysteine Endopeptidases/Genetics
  • Hla-A2 Antigen/Genetics
  • Hla-A2 Antigen/Immunology
  • Humans
  • Lymph Nodes/Immunology
  • Lymph Nodes/Pathology
  • Male
  • Melanoma/Immunology
  • Middle Aged
  • Multienzyme Complexes/Deficiency
  • Multienzyme Complexes/Genetics
  • Mutation
  • Neoplasm Proteins/Immunology
  • Proteasome Endopeptidase Complex
  • T-Lymphocytes
  • Cytotoxic/Immunology
  • Biology
  • Chemistry
  • Medicine


Tumor-reactive T cells play an important role in cancer immunosurveillance. Applying the multimer technology, we report here an unexpected high frequency of Melan-A-specific CTLs in a melanoma patient with progressive lymph node metastases, consisting of 18 and 12.8% of total peripheral blood and tumor-infiltrating CD8+ T cells, respectively. Melan-A-specific CTLs revealed a high cytolytic activity against allogeneic Melan-A-expressing target cells but failed to kill the autologous tumor cells. Loading of the tumor cells with Melan-A peptide reversed the resistance to killing, suggesting impaired function of the MHC class I antigen processing and presentation pathway. Mutations of the coding region of the HLA-A2 binding Melan-A26-35 peptide or down-regulation of the MHC class I heavy chain, the antigenic peptide TAP, and tapasin could be excluded. However, PCR and immunohistochemical analysis revealed a deficiency of the immunoproteasomes low molecular weight protein 2 and low molecular weight protein 7 in the primary tumor cells, which affects the quantity and quality of generated T-cell epitopes and might explain the resistance to killing. This is supported by our data, demonstrating that the resistance to killing can be partially reversed by pre-exposure of the tumor cells to IFN-gamma, which is known to induce the immunoproteasomes. Overall, this is the first report of an extremely high frequency of tumor-specific CTLs that exhibit competent T-cell-effector functions but fail to lyse the autologous tumor cells. Immunotherapeutic approaches should not only focus on the induction of a robust antitumor immune response, but should also have to target tumor immune escape mechanisms.

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