High frequency of functionally active Melan-a-specific T cells in a patient with progressive immunoproteasome-deficient melanoma.
Details
Serval ID
serval:BIB_81064933F919
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
High frequency of functionally active Melan-a-specific T cells in a patient with progressive immunoproteasome-deficient melanoma.
Journal
Cancer Research
ISSN
0008-5472, 0008-5472[linking]
Publication state
Published
Issued date
2004
Volume
64
Number
17
Pages
6319-6326
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
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.
Keywords
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
Pubmed
Web of science
Open Access
Yes
Create date
28/01/2008 11:28
Last modification date
20/08/2019 14:41