Abstract 6166: Identification of immunogenic cell death inducers from Komaroviquinone (KQN)-derived compounds

Abstract Background: Immunogenic Cell Death (ICD) is a type of cell death accompanied by expression of calreticulin (CRT) and release of ATP and HMGB1, which is induced by photodynamic therapies (PDT), oncolytic viruses and several chemotherapeutic drugs. ICD could enhance the therapeutic effect of other immunotherapies through maturation of dendritic cells and activation of T cells. Multiple myeloma (MM) remains incurable despite of the development of novel therapies including several immunotherapies, such as CAR-T therapy. Therefore, we tried to detect novel drugs which can induce immunogenic cell death in MM cells using a library of Komaroviquinone(KQN) - derived compounds (GTN compounds). We also investigated the mechanism of the ICD induced in MM cells. Methods: We screened 38 kinds of GTN compounds. MUM24 cell line was treated with each of GTN compounds and the cell surface expression of calreticulin (CRT) and release of ATP and HMGB1 were evaluated by FACS, ENLITEN ATP Assay System® and Western Blotting respectively. We also examined the effect of candidate drugs on differentiation of dendritic cells (DCs) by coculture of human monocyte-derived DCs with drug-treated MUM24 and detection of the expression of CD80, CD83 and HLA-DR by FACS. Production of ROS was also measured by CM-H2DCFDA assay. Finally, RNA sequence analysis was conducted using total RNA extracted from 4 MM cell lines treated with GTN057. Results: Five out of 38 GTN derivatives could induce ICD in MM cells. When DCs were co-cultured with drug-treated MUM24, increased expression of HLA-DR, CD80 and CD83 were observed with GTN025, 040, 057. Cell surface expression of CRT was not abrogated by antioxidants, despite that those compounds facilitated ROS production. Furthermore, analysis of RNA sequences revealed that ER-stress-related genes were up-regulated by GTN057. Conclusions: Our results suggest that some of GTN compounds effectively induce ICD in MM cells. Although further investigation using in vivo model is needed, those compounds might have synergistic effects when used in combination with other immunotherapies. Citation Format: Maiko Matsushita, Koki Kurita, Taisei Fujinami, Himari Yamada, Yusuke Yamamoto, Yutaka Suto. Identification of immunogenic cell death inducers from Komaroviquinone (KQN)-derived compounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6166.