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Sci Rep. 2016 May 4;6:25208. doi: 10.1038/srep25208.

Exposure to Melan-A/MART-126-35 tumor epitope specific CD8(+)T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS).

Author information

Charité-Universitätsmedizin Berlin, Institut für Biochemie, Charité-Platz 1/ Virchowweg 6, 10117 Berlin, Germany.
Department of Dermatology, University Hospital, University Duisburg-Essen and German Cancer Consortium (DKTK), Hufelandstr. 55, 45122 Essen, Germany.
Charité-Universitätsmedizin Berlin, Klinik für Dermatologie, Venerologie und Allergologie, Charité Platz 1, 10117 Berlin, Germany.
Berlin Institute of Health Kapelle-Ufer 2 10117 Berlin, Germany.
Institut für Molekulare und Klinische Immunologie, Medizinische Fakultät der Otto-von-Guericke-Universität Magdeburg, Leipzigerstr. 44, 39120 Magdeburg, Germany.


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.

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