title: Exposure to Melan-A/MART-126-35 tumor epitope specific CD8(+)T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS).
abstract: Efficient processing of target antigens by the ubiquitin-proteasome-system (UPS) is essential for treatment of cancers by T cell therapies. However, immune escape due to altered expression of IFN-γ-inducible components of the antigen presentation machinery and consequent inefficient processing of HLA-dependent tumor epitopes can be one important reason for failure of such therapies. Here, we show that short-term co-culture of Melan-A/MART-1 tumor antigen-expressing melanoma cells with Melan-A/MART-126-35-specific cytotoxic T lymphocytes (CTL) led to resistance against CTL-induced lysis because of impaired Melan-A/MART-126-35 epitope processing. Interestingly, deregulation of p97/VCP expression, which is an IFN-γ-independent component of the UPS and part of the ER-dependent protein degradation pathway (ERAD), was found to be essentially involved in the observed immune escape. In support, our data demonstrate that re-expression of p97/VCP in Melan-A/MART-126-35 CTL-resistant melanoma cells completely restored immune recognition by Melan-A/MART-126-35 CTL. In conclusion, our experiments show that impaired expression of IFN-γ-independent components of the UPS can exert rapid immune evasion of tumor cells and suggest that tumor antigens processed by distinct UPS degradation pathways should be simultaneously targeted in T cell therapies to restrict the likelihood of immune evasion due to impaired antigen processing.
authors.affiliation: Charité-Universitätsmedizin Berlin, Institut für Biochemie, Charité-Platz 1/ Virchowweg 6, 10117 Berlin, Germany.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ebstein
authors.affiliation: Charité-Universitätsmedizin Berlin, Institut für Biochemie, Charité-Platz 1/ Virchowweg 6, 10117 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Keller
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen and German Cancer Consortium (DKTK), Hufelandstr. 55, 45122 Essen, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Paschen
authors.affiliation: Charité-Universitätsmedizin Berlin, Klinik für Dermatologie, Venerologie und Allergologie, Charité Platz 1, 10117 Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Walden
authors.affiliation: Charité-Universitätsmedizin Berlin, Institut für Biochemie, Charité-Platz 1/ Virchowweg 6, 10117 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Seeger
authors.affiliation: Charité-Universitätsmedizin Berlin, Institut für Biochemie, Charité-Platz 1/ Virchowweg 6, 10117 Berlin, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Bürger
authors.affiliation: Charité-Universitätsmedizin Berlin, Institut für Biochemie, Charité-Platz 1/ Virchowweg 6, 10117 Berlin, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Krüger
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen and German Cancer Consortium (DKTK), Hufelandstr. 55, 45122 Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Charité-Universitätsmedizin Berlin, Institut für Biochemie, Charité-Platz 1/ Virchowweg 6, 10117 Berlin, Germany.|Berlin Institute of Health Kapelle-Ufer 2 10117 Berlin, Germany.
authors.forename: Peter-M
authors.initials: PM
authors.lastname: Kloetzel
authors.affiliation: Charité-Universitätsmedizin Berlin, Institut für Biochemie, Charité-Platz 1/ Virchowweg 6, 10117 Berlin, Germany.|Institut für Molekulare und Klinische Immunologie, Medizinische Fakultät der Otto-von-Guericke-Universität Magdeburg, Leipzigerstr. 44, 39120 Magdeburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Seifert
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018920:Coculture Techniques; D000939:Epitopes / Q000276:immunology*; D057131:Immune Evasion; D058965:MART-1 Antigen / Q000276:immunology*; D008544:Melanocytes / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D000939:Epitopes; D058965:MART-1 Antigen; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex