Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy
Name
2744.full.pdf
Description
Published version
Size
2.31 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
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
Date Issued
September 2018
Journal
Journal of Immunology
Publisher
American Association of Immunologists
Citation
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
Version
Final published version
Abstract
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.4049/jimmunol.1800885
