Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells
The functional plasticity and anti-tumor potential of human γδ T cells have been widely studied. However, the epigenetic regulation of γδ T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VP...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00569/full |
| _version_ | 1828518800765485056 |
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| author | Jaydeep Bhat Samuel Dubin Alexandra Dananberg Elgar Susanne Quabius Elgar Susanne Quabius Juergen Fritsch C. Marie Dowds C. Marie Dowds Ankit Saxena Guranda Chitadze Marcus Lettau Dieter Kabelitz |
| author_facet | Jaydeep Bhat Samuel Dubin Alexandra Dananberg Elgar Susanne Quabius Elgar Susanne Quabius Juergen Fritsch C. Marie Dowds C. Marie Dowds Ankit Saxena Guranda Chitadze Marcus Lettau Dieter Kabelitz |
| author_sort | Jaydeep Bhat |
| collection | DOAJ |
| description | The functional plasticity and anti-tumor potential of human γδ T cells have been widely studied. However, the epigenetic regulation of γδ T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VPA) significantly enhanced the expression and/or release of the NKG2D ligands MICA, MICB and ULBP-2, but not ULBP-1 in the pancreatic carcinoma cell line Panc89 and the prostate carcinoma cell line PC-3. Under in vitro tumor co-culture conditions, the expression of full length and the truncated form of the NKG2D receptor in γδ T cells was significantly downregulated. Furthermore, using a newly established flow cytometry-based method to analyze histone acetylation (H3K9ac) in γδ T cells, we showed constitutive H3K9aclow and inducible H3K9achigh expression in Vδ2 T cells. The detailed analysis of H3K9aclow Vδ2 T cells revealed a significant reversion of TEMRA to TEM phenotype during in vitro co-culture with pancreatic ductal adenocarcinoma cells. Our study uncovers novel mechanisms of how epigenetic modifiers modulate γδ T-cell differentiation during interaction with tumor cells. This information is important when considering combination therapy of VPA with the γδ T-cell-based immunotherapy for the treatment of certain types of cancer. |
| first_indexed | 2024-12-11T19:00:53Z |
| format | Article |
| id | doaj.art-68e6aa2d09404ae286c0bba6866dc74d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T19:00:53Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-68e6aa2d09404ae286c0bba6866dc74d2022-12-22T00:54:01ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-03-011010.3389/fimmu.2019.00569440486Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor CellsJaydeep Bhat0Samuel Dubin1Alexandra Dananberg2Elgar Susanne Quabius3Elgar Susanne Quabius4Juergen Fritsch5C. Marie Dowds6C. Marie Dowds7Ankit Saxena8Guranda Chitadze9Marcus Lettau10Dieter Kabelitz11Institute of Immunology, University Hospital Schleswig-Holstein, Kiel, GermanyInstitute of Immunology, University Hospital Schleswig-Holstein, Kiel, GermanyInstitute of Immunology, University Hospital Schleswig-Holstein, Kiel, GermanyInstitute of Immunology, University Hospital Schleswig-Holstein, Kiel, GermanyDepartment of Oto-Rhino-Laryngology, University Hospital Schleswig-Holstein, Kiel, GermanyInstitute of Immunology, University Hospital Schleswig-Holstein, Kiel, GermanyInstitute of Immunology, University Hospital Schleswig-Holstein, Kiel, GermanyInstitute of Clinical Molecular Biology, Kiel University, Kiel, GermanyNational Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United StatesInstitute of Immunology, University Hospital Schleswig-Holstein, Kiel, GermanyInstitute of Immunology, University Hospital Schleswig-Holstein, Kiel, GermanyInstitute of Immunology, University Hospital Schleswig-Holstein, Kiel, GermanyThe functional plasticity and anti-tumor potential of human γδ T cells have been widely studied. However, the epigenetic regulation of γδ T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VPA) significantly enhanced the expression and/or release of the NKG2D ligands MICA, MICB and ULBP-2, but not ULBP-1 in the pancreatic carcinoma cell line Panc89 and the prostate carcinoma cell line PC-3. Under in vitro tumor co-culture conditions, the expression of full length and the truncated form of the NKG2D receptor in γδ T cells was significantly downregulated. Furthermore, using a newly established flow cytometry-based method to analyze histone acetylation (H3K9ac) in γδ T cells, we showed constitutive H3K9aclow and inducible H3K9achigh expression in Vδ2 T cells. The detailed analysis of H3K9aclow Vδ2 T cells revealed a significant reversion of TEMRA to TEM phenotype during in vitro co-culture with pancreatic ductal adenocarcinoma cells. Our study uncovers novel mechanisms of how epigenetic modifiers modulate γδ T-cell differentiation during interaction with tumor cells. This information is important when considering combination therapy of VPA with the γδ T-cell-based immunotherapy for the treatment of certain types of cancer.https://www.frontiersin.org/article/10.3389/fimmu.2019.00569/fullgamma/delta T cellsHDAC inhibitor(s)histone acetylationNKG2Dmemory T cellstumor microenvironment |
| spellingShingle | Jaydeep Bhat Samuel Dubin Alexandra Dananberg Elgar Susanne Quabius Elgar Susanne Quabius Juergen Fritsch C. Marie Dowds C. Marie Dowds Ankit Saxena Guranda Chitadze Marcus Lettau Dieter Kabelitz Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells Frontiers in Immunology gamma/delta T cells HDAC inhibitor(s) histone acetylation NKG2D memory T cells tumor microenvironment |
| title | Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells |
| title_full | Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells |
| title_fullStr | Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells |
| title_full_unstemmed | Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells |
| title_short | Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells |
| title_sort | histone deacetylase inhibitor modulates nkg2d receptor expression and memory phenotype of human gamma delta t cells upon interaction with tumor cells |
| topic | gamma/delta T cells HDAC inhibitor(s) histone acetylation NKG2D memory T cells tumor microenvironment |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00569/full |
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