ABSTRACT
Bromo- and extra-terminal domain (BET) inhibitors represent potential therapeutic approaches in solid and hematological malignancies that are currently analyzed in several clinical trials. Additionally, BET are involved in the epigenetic regulation of immune responses by macrophages and dendritic cells (DCs), that play a central role in the regulation of immune responses, indicating that cancer treatment with BET inhibitors can promote immunosuppressive effects. The aim of this study was to further characterize the effects of selective BET inhibition by JQ1 on DC maturation and DC-mediated antigen-specific T-cell responses. Selective BET inhibition by JQ1 impairs LPS-induced DC maturation and inhibits the migrational activity of DCs, while antigen uptake is not affected. JQ1-treated DCs show reduced ability to induce antigen-specific T-cell proliferation. Moreover, antigen-specific T cells co-cultured with JQ1-treated DCs exhibit an inactive phenotype and reduced cytokine production. JQ1-treated mice show reduced immune responses in vivo to sublethal doses of LPS, characterized by a reduced white blood cell count, an immature phenotype of splenic DCs and T cells and lower blood levels of IL-6. In our study, we demonstrate that selective BET inhibition by JQ1, a drug currently tested in clinical trials for malignant diseases, has profound effects on DC maturation and DC-mediated antigen-specific T-cell responses. These immunosuppressive effects can result in the induction of possible infectious side effects in cancer treatments. In addition, based on our results, these compounds should not be used in combinatorial regimes using immunotherapeutic approaches such as check point inhibitors, T-cell therapies, or vaccines.