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dc.contributor.authorBadamchi-Zadeh, Alexander
dc.contributor.authorMoynihan, Kelly Dare
dc.contributor.authorLarocca, Rafael A.
dc.contributor.authorAid, Malika
dc.contributor.authorProvine, Nicholas M.
dc.contributor.authorIampietro, M. Justin
dc.contributor.authorKinnear, Ekaterina
dc.contributor.authorPenaloza-MacMaster, Pablo
dc.contributor.authorAbbink, Peter
dc.contributor.authorBlass, Eryn
dc.contributor.authorTregoning, John S.
dc.contributor.authorIrvine, Darrell J
dc.contributor.authorBarouch, Dan H.
dc.date.accessioned2020-07-17T19:40:19Z
dc.date.available2020-07-17T19:40:19Z
dc.date.issued2018-09
dc.date.submitted2018-06
dc.identifier.issn0022-1767
dc.identifier.issn1550-6606
dc.identifier.urihttps://hdl.handle.net/1721.1/126247
dc.description.abstractThe 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.en_US
dc.language.isoen
dc.publisherAmerican Association of Immunologistsen_US
dc.relation.isversionofhttp://dx.doi.org/10.4049/jimmunol.1800885en_US
dc.rightsArticle 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.en_US
dc.sourceJournal of Immunologyen_US
dc.titleCombined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacyen_US
dc.typeArticleen_US
dc.identifier.citationBadamchi-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, Incen_US
dc.contributor.departmentDavid H. Koch Institute for Integrative Cancer Research at MITen_US
dc.relation.journalJournal of Immunologyen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2020-03-11T11:56:05Z
dspace.date.submission2020-03-11T11:56:08Z
mit.journal.volume201en_US
mit.journal.issue9en_US
mit.licensePUBLISHER_POLICY


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