The landscape of CD28, CD80, CD86, CTLA4, and ICOS DNA methylation in head and neck squamous cell carcinomas
CTLA-4 blocking therapeutic antibodies are currently under investigation in head and neck squamous cell carcinoma (HNSCC). A better understanding of the epigenetic regulation of the CD28 superfamily members CD28, CTLA-4, and ICOS and their B7 ligands, CD80 and CD86, could support the development of...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-11-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2020.1754675 |
| _version_ | 1797678886994051072 |
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| author | Luka de Vos Ingela Grünwald Emma Grace Bawden Jörn Dietrich Kathrin Scheckenbach Constanze Wiek Romina Zarbl Friedrich Bootz Jennifer Landsberg Dimo Dietrich |
| author_facet | Luka de Vos Ingela Grünwald Emma Grace Bawden Jörn Dietrich Kathrin Scheckenbach Constanze Wiek Romina Zarbl Friedrich Bootz Jennifer Landsberg Dimo Dietrich |
| author_sort | Luka de Vos |
| collection | DOAJ |
| description | CTLA-4 blocking therapeutic antibodies are currently under investigation in head and neck squamous cell carcinoma (HNSCC). A better understanding of the epigenetic regulation of the CD28 superfamily members CD28, CTLA-4, and ICOS and their B7 ligands, CD80 and CD86, could support the development of biomarkers for response prediction to anti-CTLA-4 immunotherapy. We investigated methylation of the encoding genes CD28, CTLA4, ICOS, CD80, and CD86 at single CpG resolution (51 CpG sites) in a cohort of HNSCC (N = 528) and normal adjacent tissue samples (N = 50) provided by The Cancer Genome Research Atlas, in isolated blood leukocytes from healthy individuals (N = 28), and HNSCC cell lines (N = 39). We analysed methylation levels with regard to mRNA expression, overall survival, mutational load, interferon-γ signature, and signatures of immune cell infiltrates. Depending on the location of the CpG sites (promoter, promoter flank, gene body, and intergenic sites), we found significant differences in methylation levels among isolated leukocytes, between leukocytes and HNSCC cell lines, and among HNSCCs. Methylation of all analysed genes correlated inversely or positively with mRNA expression, depending on the CpG site. CD28, CTLA4, and ICOS revealed almost identical correlation patterns. Furthermore, we found significant correlations with survival and features of response to immunotherapy, i.e. interferon-γ signature, signatures of tumour infiltrating immune cells, and mutational load. Our results suggest CD28, CTLA4, ICOS, CD80, and CD86 expression levels are epigenetically co-regulated by DNA methylation. This study provides rationale to test their DNA methylation as potential biomarker for prediction of response to CTLA-4 immune checkpoint inhibitors. |
| first_indexed | 2024-03-11T23:06:27Z |
| format | Article |
| id | doaj.art-57166499a8bc49da998576e00116f167 |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:06:27Z |
| publishDate | 2020-11-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-57166499a8bc49da998576e00116f1672023-09-21T13:09:23ZengTaylor & Francis GroupEpigenetics1559-22941559-23082020-11-0115111195121210.1080/15592294.2020.17546751754675The landscape of CD28, CD80, CD86, CTLA4, and ICOS DNA methylation in head and neck squamous cell carcinomasLuka de Vos0Ingela Grünwald1Emma Grace Bawden2Jörn Dietrich3Kathrin Scheckenbach4Constanze Wiek5Romina Zarbl6Friedrich Bootz7Jennifer Landsberg8Dimo Dietrich9Rheinische Friedrich-Wilhelms-Universität BonnRheinische Friedrich-Wilhelms-Universität BonnThe University of Melbourne at the Peter Doherty Institute for Infection & ImmunityRheinische Friedrich-Wilhelms-Universität BonnUniversity Hospital DüsseldorfUniversity Hospital DüsseldorfRheinische Friedrich-Wilhelms-Universität BonnRheinische Friedrich-Wilhelms-Universität BonnUniversity Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität BonnRheinische Friedrich-Wilhelms-Universität BonnCTLA-4 blocking therapeutic antibodies are currently under investigation in head and neck squamous cell carcinoma (HNSCC). A better understanding of the epigenetic regulation of the CD28 superfamily members CD28, CTLA-4, and ICOS and their B7 ligands, CD80 and CD86, could support the development of biomarkers for response prediction to anti-CTLA-4 immunotherapy. We investigated methylation of the encoding genes CD28, CTLA4, ICOS, CD80, and CD86 at single CpG resolution (51 CpG sites) in a cohort of HNSCC (N = 528) and normal adjacent tissue samples (N = 50) provided by The Cancer Genome Research Atlas, in isolated blood leukocytes from healthy individuals (N = 28), and HNSCC cell lines (N = 39). We analysed methylation levels with regard to mRNA expression, overall survival, mutational load, interferon-γ signature, and signatures of immune cell infiltrates. Depending on the location of the CpG sites (promoter, promoter flank, gene body, and intergenic sites), we found significant differences in methylation levels among isolated leukocytes, between leukocytes and HNSCC cell lines, and among HNSCCs. Methylation of all analysed genes correlated inversely or positively with mRNA expression, depending on the CpG site. CD28, CTLA4, and ICOS revealed almost identical correlation patterns. Furthermore, we found significant correlations with survival and features of response to immunotherapy, i.e. interferon-γ signature, signatures of tumour infiltrating immune cells, and mutational load. Our results suggest CD28, CTLA4, ICOS, CD80, and CD86 expression levels are epigenetically co-regulated by DNA methylation. This study provides rationale to test their DNA methylation as potential biomarker for prediction of response to CTLA-4 immune checkpoint inhibitors.http://dx.doi.org/10.1080/15592294.2020.1754675cd28cd80cd86ctla4icosdna methylationimmune checkpointhnsccprognosistumour microenvironmenthpv |
| spellingShingle | Luka de Vos Ingela Grünwald Emma Grace Bawden Jörn Dietrich Kathrin Scheckenbach Constanze Wiek Romina Zarbl Friedrich Bootz Jennifer Landsberg Dimo Dietrich The landscape of CD28, CD80, CD86, CTLA4, and ICOS DNA methylation in head and neck squamous cell carcinomas Epigenetics cd28 cd80 cd86 ctla4 icos dna methylation immune checkpoint hnscc prognosis tumour microenvironment hpv |
| title | The landscape of CD28, CD80, CD86, CTLA4, and ICOS DNA methylation in head and neck squamous cell carcinomas |
| title_full | The landscape of CD28, CD80, CD86, CTLA4, and ICOS DNA methylation in head and neck squamous cell carcinomas |
| title_fullStr | The landscape of CD28, CD80, CD86, CTLA4, and ICOS DNA methylation in head and neck squamous cell carcinomas |
| title_full_unstemmed | The landscape of CD28, CD80, CD86, CTLA4, and ICOS DNA methylation in head and neck squamous cell carcinomas |
| title_short | The landscape of CD28, CD80, CD86, CTLA4, and ICOS DNA methylation in head and neck squamous cell carcinomas |
| title_sort | landscape of cd28 cd80 cd86 ctla4 and icos dna methylation in head and neck squamous cell carcinomas |
| topic | cd28 cd80 cd86 ctla4 icos dna methylation immune checkpoint hnscc prognosis tumour microenvironment hpv |
| url | http://dx.doi.org/10.1080/15592294.2020.1754675 |
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