Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy
The combined inhibition of histone deacetylases (HDAC) and the proteins of the bromodomain and extraterminal (BET) family have recently shown therapeutic efficacy against melanoma, pancreatic ductal adenocarcinoma, testicular, and lymphoma cancers in murine studies. However, in such studies, the rol...
| Main Authors: | , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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American Association of Immunologists
2020
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| Online Access: | https://hdl.handle.net/1721.1/126247 |
| _version_ | 1811088438228680704 |
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| author | Badamchi-Zadeh, Alexander Moynihan, Kelly Dare Larocca, Rafael A. Aid, Malika Provine, Nicholas M. Iampietro, M. Justin Kinnear, Ekaterina Penaloza-MacMaster, Pablo Abbink, Peter Blass, Eryn Tregoning, John S. Irvine, Darrell J Barouch, Dan H. |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Badamchi-Zadeh, Alexander Moynihan, Kelly Dare Larocca, Rafael A. Aid, Malika Provine, Nicholas M. Iampietro, M. Justin Kinnear, Ekaterina Penaloza-MacMaster, Pablo Abbink, Peter Blass, Eryn Tregoning, John S. Irvine, Darrell J Barouch, Dan H. |
| author_sort | Badamchi-Zadeh, Alexander |
| collection | MIT |
| description | The combined inhibition of histone deacetylases (HDAC) and the proteins of the bromodomain and extraterminal (BET) family have recently shown therapeutic efficacy against melanoma, pancreatic ductal adenocarcinoma, testicular, and lymphoma cancers in murine studies. However, in such studies, the role of the immune system in therapeutically controlling these cancers has not been explored. We sought to investigate the effect of the HDAC inhibitor romidepsin (RMD) and the BET inhibitor IBET151, both singly and in combination, on vaccine-elicited immune responses. C57BL/6 mice were immunized with differing vaccine systems (adenoviral, protein) in prime-boost regimens under treatment with RMD, IBET151, or RMD+IBET151. The combined administration of RMD+IBET151 during vaccination resulted in a significant increase in the frequency and number of Ag-specific CD8+ T cells. RMD+IBET151 treatment significantly increased the frequency of vaccine-elicited IFN-γ+ splenic CD8+ T cells and conferred superior therapeutic and prophylactic protection against B16-OVA melanoma. RNA sequencing analyses revealed strong transcriptional similarity between RMD+IBET151 and untreated Ag-specific CD8+ T cells except in apoptosis and IL-6 signaling-related genes that were differentially expressed. Serum IL-6 was significantly increased in vivo following RMD+IBET151 treatment, with recombinant IL-6 administration replicating the effect of RMD+IBET151 treatment on vaccine-elicited CD8+ T cell responses. IL-6 sufficiency for protection was not assessed. Combined HDAC and BET inhibition resulted in greater vaccine-elicited CD8+ T cell responses and enhanced therapeutic and prophylactic protection against B16-OVA melanoma. Increased IL-6 production and the differential expression of pro-and anti-apoptotic genes following RMD+IBET151 treatment are likely contributors to the enhanced cancer vaccine responses. |
| first_indexed | 2024-09-23T14:02:12Z |
| format | Article |
| id | mit-1721.1/126247 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:02:12Z |
| publishDate | 2020 |
| publisher | American Association of Immunologists |
| record_format | dspace |
| spelling | mit-1721.1/1262472022-09-28T17:54:22Z Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy Badamchi-Zadeh, Alexander Moynihan, Kelly Dare Larocca, Rafael A. Aid, Malika Provine, Nicholas M. Iampietro, M. Justin Kinnear, Ekaterina Penaloza-MacMaster, Pablo Abbink, Peter Blass, Eryn Tregoning, John S. Irvine, Darrell J Barouch, Dan H. Koch Institute for Integrative Cancer Research at MIT The combined inhibition of histone deacetylases (HDAC) and the proteins of the bromodomain and extraterminal (BET) family have recently shown therapeutic efficacy against melanoma, pancreatic ductal adenocarcinoma, testicular, and lymphoma cancers in murine studies. However, in such studies, the role of the immune system in therapeutically controlling these cancers has not been explored. We sought to investigate the effect of the HDAC inhibitor romidepsin (RMD) and the BET inhibitor IBET151, both singly and in combination, on vaccine-elicited immune responses. C57BL/6 mice were immunized with differing vaccine systems (adenoviral, protein) in prime-boost regimens under treatment with RMD, IBET151, or RMD+IBET151. The combined administration of RMD+IBET151 during vaccination resulted in a significant increase in the frequency and number of Ag-specific CD8+ T cells. RMD+IBET151 treatment significantly increased the frequency of vaccine-elicited IFN-γ+ splenic CD8+ T cells and conferred superior therapeutic and prophylactic protection against B16-OVA melanoma. RNA sequencing analyses revealed strong transcriptional similarity between RMD+IBET151 and untreated Ag-specific CD8+ T cells except in apoptosis and IL-6 signaling-related genes that were differentially expressed. Serum IL-6 was significantly increased in vivo following RMD+IBET151 treatment, with recombinant IL-6 administration replicating the effect of RMD+IBET151 treatment on vaccine-elicited CD8+ T cell responses. IL-6 sufficiency for protection was not assessed. Combined HDAC and BET inhibition resulted in greater vaccine-elicited CD8+ T cell responses and enhanced therapeutic and prophylactic protection against B16-OVA melanoma. Increased IL-6 production and the differential expression of pro-and anti-apoptotic genes following RMD+IBET151 treatment are likely contributors to the enhanced cancer vaccine responses. 2020-07-17T19:40:19Z 2020-07-17T19:40:19Z 2018-09 2018-06 2020-03-11T11:56:05Z Article http://purl.org/eprint/type/JournalArticle 0022-1767 1550-6606 https://hdl.handle.net/1721.1/126247 Badamchi-Zadeh, Alexander et al. "Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy." Journal of Immunology 201, 9 (September 2018): 2744-2752 © 2018 The American Association of Immunologists, Inc en http://dx.doi.org/10.4049/jimmunol.1800885 Journal of Immunology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Association of Immunologists Journal of Immunology |
| spellingShingle | Badamchi-Zadeh, Alexander Moynihan, Kelly Dare Larocca, Rafael A. Aid, Malika Provine, Nicholas M. Iampietro, M. Justin Kinnear, Ekaterina Penaloza-MacMaster, Pablo Abbink, Peter Blass, Eryn Tregoning, John S. Irvine, Darrell J Barouch, Dan H. Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy |
| title | Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy |
| title_full | Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy |
| title_fullStr | Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy |
| title_full_unstemmed | Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy |
| title_short | Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy |
| title_sort | combined hdac and bet inhibition enhances melanoma vaccine immunogenicity and efficacy |
| url | https://hdl.handle.net/1721.1/126247 |
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