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

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

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 HL...

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Main Authors: Ebstein, Frédéric, Keller, Martin, Paschen, Annette, Walden, Peter, Seeger, Michael, Bürger, Elke, Krüger, Elke, Schadendorf, Dirk, Kloetzel, Peter-M., Seifert, Ulrike
Format: Online
Language:English
Published: Nature Publishing Group 2016
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855237/
id pubmed-4855237
recordtype oai_dc
spelling pubmed-48552372016-05-18 Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS) Ebstein, Frédéric Keller, Martin Paschen, Annette Walden, Peter Seeger, Michael Bürger, Elke Krüger, Elke Schadendorf, Dirk Kloetzel, Peter-M. Seifert, Ulrike Article 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. Nature Publishing Group 2016-05-04 /pmc/articles/PMC4855237/ /pubmed/27143649 http://dx.doi.org/10.1038/srep25208 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Ebstein, Frédéric
Keller, Martin
Paschen, Annette
Walden, Peter
Seeger, Michael
Bürger, Elke
Krüger, Elke
Schadendorf, Dirk
Kloetzel, Peter-M.
Seifert, Ulrike
spellingShingle Ebstein, Frédéric
Keller, Martin
Paschen, Annette
Walden, Peter
Seeger, Michael
Bürger, Elke
Krüger, Elke
Schadendorf, Dirk
Kloetzel, Peter-M.
Seifert, Ulrike
Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS)
author_facet Ebstein, Frédéric
Keller, Martin
Paschen, Annette
Walden, Peter
Seeger, Michael
Bürger, Elke
Krüger, Elke
Schadendorf, Dirk
Kloetzel, Peter-M.
Seifert, Ulrike
author_sort Ebstein, Frédéric
title Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS)
title_short Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS)
title_full Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS)
title_fullStr Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS)
title_full_unstemmed Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS)
title_sort exposure to melan-a/mart-126-35 tumor epitope specific cd8+t cells reveals immune escape by affecting the ubiquitin-proteasome system (ups)
description 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.
publisher Nature Publishing Group
publishDate 2016
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855237/
_version_ 1613574888639954944

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