title: High frequency of functionally active Melan-a-specific T cells in a patient with progressive immunoproteasome-deficient melanoma.
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.
authors.affiliation: Department of Hematology/Oncology, University of Regensburg, Regensburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Meidenbauer
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
authors.forename: Mikaël J
authors.initials: MJ
authors.lastname: Pittet
authors.forename: Monika
authors.initials: M
authors.lastname: Laumer
authors.forename: Sandra
authors.initials: S
authors.lastname: Vogl
authors.forename: Jana
authors.initials: J
authors.lastname: Heymann
authors.forename: Michael
authors.initials: M
authors.lastname: Rehli
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
authors.forename: Stephan
authors.initials: S
authors.lastname: Schwarz
authors.forename: Frederique-Anne
authors.initials: FA
authors.lastname: Le Gal
authors.forename: Pierre Y
authors.initials: PY
authors.lastname: Dietrich
authors.forename: Reinhard
authors.initials: R
authors.lastname: Andreesen
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Andreas
authors.initials: A
authors.lastname: Mackensen
mesh_terms: D000951:Antigens, Neoplasm; D003546:Cysteine Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000276:immunology*; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D009154:Mutation; D009363:Neoplasm Proteins / Q000276:immunology*; D046988:Proteasome Endopeptidase Complex; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex