Combined HDAC and BET inhibition to enhance cancer vaccine-elicited T-cell responses.
Badamchi-Zadeh A., Moynihan KD., Provine NM., Larocca R., Irvine DJ., Barouch DH.
e14632 Background: The combined inhibition of histone deacetylases (HDAC) and the proteins of the bromo and extra terminal (BET) family have recently shown therapeutic efficacy against pancreatic ductal adenocarcinoma, melanoma and lymphoma cancers in murine studies. However, in these studies the role of the immune system in therapeutically controlling these cancers was not explored. Methods: We sought to investigate the effect of the HDAC inhibitor romidepsin (RMD) and the BET inhibitor I-BET151, both singly and in combination, on vaccine elicited immune responses. C57Bl/6 mice were immunized with differing vaccines (Adenoviral, protein) in prime-boost regimens, under treatment with RMD, I-BET151, or RMD+I-BET151. Results: The combination RMD+I-BET151, administered during Adenoviral prime-boost vaccination, resulted in the significant increase in the frequency and number of antigen-specific CD8 T cells. RMD+I-BET151 treatment affected vaccine-elicited secondary T cell responses, significantly increasing the frequency of IFN-γ+ splenic CD8 T cells and maintaining their dual IFN-γ+TNFa+ polyfunctionality. These CD8 T cells maintained their protective ability against Listeria monocytogenes, and protected against B16-OVA challenge. The significant augmentation of vaccine elicited CD8 T cell responses under RMD+I-BET151 treatment was additionally observed following protein (OVA+CpG) prime-boost vaccination, resulting in greater protection against B16-OVA challenge and enhanced survival. T-regulatory cell (FoxP3+CD4+) frequency and total CD4 and CD8 cell numbers remained unaltered following RMD+I-BET151 treatment. Conclusions: Combined HDAC and BET inhibition resulted in greater vaccine-elicited CD8 T cell responses following immunization by multiple vaccine platforms, and enhanced protection against B16-OVA challenges. We are currently assessing immunological mechanisms of action for this combined HDAC and BET inhibition.