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

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 17; pp. 6319 - 6326
• Main Authors: MEIDENBAUER, Norbert, ZIPPELIUS, Alfred, DIETRICH, Pierre Y, ANDREESEN, Reinhard, ROMERO, Pedro, MACKENSEN, Andreas, PITTET, Mikaël J, LAUMER, Monika, VOGL, Sandra, HEYMANN, Jana, REHLI, Michael, SELIGER, Barbara, SCHWARZ, Stephan, LE GAL, Frederique-Anne
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2004
• Subjects: Antigens, Neoplasm; Antineoplastic agents; Biological and medical sciences; Cysteine Endopeptidases - deficiency; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - immunology; HLA-A2 Antigen - genetics; HLA-A2 Antigen - immunology; Humans; Lymph Nodes - immunology; Lymph Nodes - pathology; Male; MART-1 Antigen; Medical sciences; Melanoma - immunology; Middle Aged; Multienzyme Complexes - deficiency; Multienzyme Complexes - genetics; Multienzyme Complexes - immunology; Mutation; Neoplasm Proteins - immunology; Pharmacology. Drug treatments; Proteasome Endopeptidase Complex; T-Lymphocytes, Cytotoxic - immunology; Tumors; Human; Tissue specificity; Frequency; Malignant tumor; T-Lymphocyte; Malignant melanoma
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-1341

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.