Histone deacetylase inhibitors downregulate CCR4 expression and decrease mogamulizumab efficacy in CCR4-positive mature T-cell lymphomas.

4 years ago

Histone deacetylase inhibitors downregulate CCR4 expression and decrease mogamulizumab efficacy in CCR4-positive mature T-cell lymphomas.

Tagawa, Abe, Takahashi, Matsue, Ikeda, Shimizu, Kitadate

HDAC inhibitors are promising agents for various T-cell lymphomas, including cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and adult T-cell lymphoma/leukemia. CCR4 is an important therapeutic target molecule because mogamulizumab, an anti-CCR4 antibody, has shown promising efficacy against various T-cell lymphomas. In this study, we examined the in vitro synergistic effects of mogamulizumab and HDAC inhibitors against various T-cell lymphomas. First, we examined the expression of CCR4 mRNA and surface CCR4 in various T-cell lymphoma cell lines and found it was downregulated upon treatment with vorinostat, a pan-HDAC inhibitor. Next, we used isoform-specific HDAC inhibitors and siRNAs to determine the HDAC isoform involved in the regulation of CCR4, and demonstrated that romidepsin, a class I selective HDAC inhibitor, reduced CCR4 most efficiently. Moreover, among class I HDACs, the HDAC2 knockdown led to a reduction of CCR4 in lymphoma cells, suggesting that CCR4 expression is mainly regulated by HDAC2. When we examined the CCR4 expression in skin samples from primary cutaneous T-cell lymphoma, obtained from the same patients before and after vorinostat treatment, we found that CCR4 expression was greatly reduced after treatment. Finally, when we conducted an antibody-dependent cell-mediated cytotoxicity assay with mogamulizumab by using various lymphoma cells, we found that the efficacy of mogamulizumab was significantly reduced by pretreatment with vorinostat. Altogether, our results suggest that the primary use of HDAC inhibitors before treatment of mogamulizumab might not be suitable to obtain synergistic effects. Moreover, these results provide potential implications for optimal therapeutic sequences in various CCR4 positive T-cell lymphomas.

Publisher URL: http://doi.org/10.3324/haematol.2017.177279

DOI: 10.3324/haematol.2017.177279