Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma
Abstract Merkel cell carcinoma (MCC) is a rare and aggressive, yet highly immunogenic skin cancer. The latter is due to its viral or UV-associated carcinogenesis. For tumor progression MCC has to escape the host’s immuno-surveillance, e.g. by loss of HLA class-I expression. Indeed, a reduced HLA cla...
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doaj-8a93f8dccd0d4f538a485c5193e1806a2020-12-08T02:36:37ZengNature Publishing GroupScientific Reports2045-23222017-05-017111110.1038/s41598-017-02608-0Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinomaCathrin Ritter0Kaiji Fan1Annette Paschen2Sine Reker Hardrup3Soldano Ferrone4Paul Nghiem5Selma Ugurel6David Schrama7Jürgen C. Becker8Department of Translational Skin Cancer Research, University Hospital EssenDepartment of Translational Skin Cancer Research, University Hospital EssenDepartment of Dermatology, University Hospital EssenDepartment of Immunology and Vaccinology, Technical University of DenmarkDepartment of Surgery, Massachusetts General Hospital, Harvard Medical SchoolDivision of Dermatology, Department of Medicine, University of WashingtonDepartment of Dermatology, University Hospital EssenDepartment of Dermatology, University Hospital WürzburgDepartment of Translational Skin Cancer Research, University Hospital EssenAbstract Merkel cell carcinoma (MCC) is a rare and aggressive, yet highly immunogenic skin cancer. The latter is due to its viral or UV-associated carcinogenesis. For tumor progression MCC has to escape the host’s immuno-surveillance, e.g. by loss of HLA class-I expression. Indeed, a reduced HLA class-I expression was observed in MCC tumor tissues and MCC cell lines. This reduced HLA class-I surface expression is caused by an impaired expression of key components of the antigen processing machinery (APM), including LMP2 and LMP7 as well as TAP1 and TAP2. Notably, experimental provisions of HLA class-I binding peptides restored HLA class-I surface expression on MCC cells. Silencing of the HLA class-I APM is due to histone deacetylation as inhibition of histone deacetylases (HDACs) not only induced acetylation of histones in the respective promoter regions but also re-expression of APM components. Thus, HDAC inhibition restored HLA class-I surface expression in vitro and in a mouse xenotransplantation model. In contrast to re-induction of HLA class-I by interferons, HDAC inhibitors did not interfere with the expression of immuno-dominant viral proteins. In summary, restoration of HLA class-I expression on MCC cells by epigenetic priming is an attractive approach to enhance therapies boosting adaptive immune responses.https://doi.org/10.1038/s41598-017-02608-0 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Cathrin Ritter Kaiji Fan Annette Paschen Sine Reker Hardrup Soldano Ferrone Paul Nghiem Selma Ugurel David Schrama Jürgen C. Becker |
spellingShingle |
Cathrin Ritter Kaiji Fan Annette Paschen Sine Reker Hardrup Soldano Ferrone Paul Nghiem Selma Ugurel David Schrama Jürgen C. Becker Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma Scientific Reports |
author_facet |
Cathrin Ritter Kaiji Fan Annette Paschen Sine Reker Hardrup Soldano Ferrone Paul Nghiem Selma Ugurel David Schrama Jürgen C. Becker |
author_sort |
Cathrin Ritter |
title |
Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma |
title_short |
Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma |
title_full |
Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma |
title_fullStr |
Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma |
title_full_unstemmed |
Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma |
title_sort |
epigenetic priming restores the hla class-i antigen processing machinery expression in merkel cell carcinoma |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-05-01 |
description |
Abstract Merkel cell carcinoma (MCC) is a rare and aggressive, yet highly immunogenic skin cancer. The latter is due to its viral or UV-associated carcinogenesis. For tumor progression MCC has to escape the host’s immuno-surveillance, e.g. by loss of HLA class-I expression. Indeed, a reduced HLA class-I expression was observed in MCC tumor tissues and MCC cell lines. This reduced HLA class-I surface expression is caused by an impaired expression of key components of the antigen processing machinery (APM), including LMP2 and LMP7 as well as TAP1 and TAP2. Notably, experimental provisions of HLA class-I binding peptides restored HLA class-I surface expression on MCC cells. Silencing of the HLA class-I APM is due to histone deacetylation as inhibition of histone deacetylases (HDACs) not only induced acetylation of histones in the respective promoter regions but also re-expression of APM components. Thus, HDAC inhibition restored HLA class-I surface expression in vitro and in a mouse xenotransplantation model. In contrast to re-induction of HLA class-I by interferons, HDAC inhibitors did not interfere with the expression of immuno-dominant viral proteins. In summary, restoration of HLA class-I expression on MCC cells by epigenetic priming is an attractive approach to enhance therapies boosting adaptive immune responses. |
url |
https://doi.org/10.1038/s41598-017-02608-0 |
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