Abstract 643: The histone deacetylase inhibitor Quisinostat augments the anti-tumor reponses of T-cells: Implications in adoptive cell therapy
Authors: Woods David M. , Sodre Andressa L. , Brayer Jason B. , Sotomayor Eduardo M. 
Published: May 2015

It has become increasingly clear that histone deacetylases (HDACs), a family of epigenetic modifiers, play intimate roles in both tumor and immune biology. Indeed, two HDAC inhibitors (HDACi) are FDA approved for the treatment of cutaneous T-cell leukemia, and various others are currently undergoing clinical trials for the treatment of both solid and hematological malignancies. Beyond direct anti-tumor effects, HDACi have shown pronounced abilities to augment the immunogenicity of tumor cells leading to an improved ant-tumor immune response. Furthermore, in addition to anti-tumor effects, several studies have demonstrated a profound ability of HDACi to tip the scale between tolerance and inflammation in antigen presenting cells, leading to enhanced T-cell activation. However, less well studied is the ability of HDACi to directly influence the function and fate of T-cells. Here we report that the HDACi JNJ-264-81585 (Quisinostat) is able to augment the pro-inflammatory phenotype of T-cells in vitro and in vivo. Quisinostat is a hydroxamic acid with potent sub-nanomolar inhibition of several HDACs, and reported anti-tumor activity. Here we report that Quisinostat has a potent HDAC inhibition in T-cells, with sub-nanomolar doses increasing histone 3 acetylation levels in a dose dependent manner. Intriguingly, when treated with Quisinostat in vitro, activated murine CD4+ and CD8+ T-cells produced significantly higher levels of the pro-inflammatory cytokines IL-2, IFN-g, and TNF. Concomitantly, treated T-cells produced decreased levels of IL-6 and IL-17. To determine the efficacy of Quisinostat at augmenting T-cell function in vivo, a novel T-cell adoptive transfer model was utilized. In this model syngeneic T-cells from B6.SJL mice were stained with the proliferation tracking dye CellTrace™ Violet and activated in the presence of Quisinostat, then subsequently adoptively transferred into sub-lethally irradiated C57BL/6 recipient mice. Analysis of proliferation of transferred T-cells showed that CD8+ T-cells treated with Quisinostat had significantly higher rates of proliferation than those treated with DMSO control. As well, in a result similar to that seen in vitro, adoptively transferred T-cells had skewing towards a predominantly CD8+ composition. Finally, T-cells treated with Quisinostat displayed a reconstitution advantage over DMSO treated cells, with higher percentages of transferred T-cells relative to endogenous T-cells. Collectively, these results demonstrate a profound and important ability of HDAC inhibition to modulate the T-cell response, highlighting a role of HDACi, particularly Quisinostat, in augmenting the efficacy of adoptive cell therapy, giving rationale for clinical investigation.

Citation Format: David M. Woods, Andressa L. Sodre, Jason B. Brayer, Eduardo M. Sotomayor. The histone deacetylase inhibitor Quisinostat augments the anti-tumor reponses of T-cells: Implications in adoptive cell therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 643. doi:10.1158/1538-7445.AM2014-643