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

Détails

ID Serval
serval:BIB_81064933F919
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
High frequency of functionally active Melan-a-specific T cells in a patient with progressive immunoproteasome-deficient melanoma.
Périodique
Cancer Research
Auteur(s)
Meidenbauer N., Zippelius A., Pittet M.J., Laumer M., Vogl S., Heymann J., Rehli M., Seliger B., Schwarz S., Le Gal F.A., Dietrich P.Y., Andreesen R., Romero P., Mackensen A.
ISSN
0008-5472, 0008-5472[linking]
Statut éditorial
Publié
Date de publication
2004
Volume
64
Numéro
17
Pages
6319-6326
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
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
Oui
Création de la notice
28/01/2008 12:28
Dernière modification de la notice
20/08/2019 15:41
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