Description:
<jats:title>Abstract</jats:title>
<jats:p>Introduction:</jats:p>
<jats:p>HDAC inhibitors mediate their anti-cancer activity at least in part via modulation of the immunogenicity of cancer cells and reactivation of effector cells of the immune system. Evaluating possible immunomodulating properties of resminostat which potentially contribute to its overall anti-tumoral effect should be investigated.</jats:p>
<jats:p>Experiments:</jats:p>
<jats:p>Resminostat was tested for its effects on mechanisms affecting the anti-tumoral immune response such as immunosuppression, immunogenicity, immunogenic cell death (ICD) and natural killer (NK) cell recognition in several cancer cell lines.</jats:p>
<jats:p>Results:</jats:p>
<jats:p>Resminostat has the potency to affect the immune response at different levels on tumor as well as immune cells. Resminostat strongly reduced the expression of immunosuppressive enzymes, IDO1 and ARG1, which deplete the tumor microenvironment of amino acids essential for T cell activity. Further, resminostat enhanced the expression of various tumor associated antigens and MHC class I molecules leading to enhanced tumor immunogenicity. This was further enhanced by upregulation of the ICD marker and dendritic cell engulfment signal Calreticulin. The additional upregulation of MHC class II molecules and co-stimulatory molecules by resminostat lead to convertion of tumor cells into so called unprofessional antigen presenting cells. Furthermore, by upregulation of NK cell activating ligands on tumor cells, resminostat increased NK cell-mediated tumor cell cytotoxicity.</jats:p>
<jats:p>Conclusion:</jats:p>
<jats:p>Resminostat displayed promising immunomodulatory effects and immune priming capacity. Thus, this novel HDAC inhibitor demonstrates potential synergistic effects with immunotherapeutics such as opsonizing antibodies (e.g. rituximab), immunostimulating agents (e.g. cytokines and TLR ligands) and immune checkpoint blockers (such as PD1/PDL1 and CTLA-4 inhibitors) which will be analyzed on functional assays and in vivo models.</jats:p>
<jats:p>Citation Format: Hella Kohlhof, Tanja Prenzel, Sevetlana Hamm, Roland Baumgartner, Matthias Borgmann, Daniel Vitt. Immunmodulatory effects of the novel HDAC inhibitor resminostat. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A70.</jats:p>