The Novel Anti-Myeloma Agent Chaetocin Enhances Tumor-Specific Dendritic Cell Response Via the Induction of Heat Shock Protein and Cancer Testis Antigens On Myeloma Cells

Dendritic cell (DC) based immunotherapy is emerging as a useful tool to treat multiple myeloma (MM). Although several tumor target antigens have been used, the clinical effectiveness of the vaccination is still limited. Chaetocin is a small molecule thiodioxopiperazine natural-product produced by Chaetomium species fungi currently in development as a candidate antimyeloma therapeutic, and has potent in vitro and in vivo activity conveyed by its ability to impose increased levels of cellular oxidative stress. Chaetocin has also been found to be used as histone methyl-transferase inhibitor with interest in the compound sufficient to kill various cancer cells. We investigated whether chaetocin could be used to induce apoptotic bodies for loading into DCs to enhance myeloma specific antitumor responses.

Chaetocin was used to induce the apoptotic U266 myeloma cells, which were used as the sources of tumor antigens to loading onto DCs to generate myeloma-specific cytotoxic T lymphocytes (CTLs).

Chaetocin showed to induce apoptotic cells mostly from tumor cells and led to increase the expression of heat shock protein 90 (HSP90) at a level comparable to bortezomib. The transfer of activating signal from chaetocin-induced tumor cells to induce DCs maturation is mediated by the exposure of HSP90 on the surface of apoptotic cells. The HSP90 inhibitor geldanamycin can block this immunogenicity. Chaetocin up-regulate the expression of cancer testis antigens MAGEA3 and MAGEC1/CT7, which are commonly expressed in MM and the potent targets for active immunotherapies. The cytokines production during uptake tumor antigens and maturation was comparable in DCs loaded with either irradiated MM cells or chaetocin-induced MM cells. However, DCs loaded with chaetocin-induced MM cells can reduce the production of an inhibitory cytokine (IL-10) after stimulation with CD40 ligand. CTLs stimulated by chaetocin-induced MM cells-loaded DCs showed the increasing of CD8⁺T cells and displayed a greater number of IFN-g-secreting cells than did those stimulated by other DCs loaded with MM cell made by other conditions.

These results indicate that anti-myeloma drug-induced apoptotic cells can be used as the source of myeloma antigens to loading onto DCs that could elicit potent anti-myeloma activity of CTLs due to the expression of heat shock proteins and cancer testis antigens as a mechanism of immunogenic death of human MM cells.

No relevant conflicts of interest to declare.