Tartrolon D Induces Immunogenic Cell Death in Melanoma

Tartrolon D (TRL) is produced by Teredinibacter turnerae, a symbiotic cellulose-degrading bacteria in shipworm gills. Immunogenic cell death (ICD) induction contributes to a better and longer-lasting response to anticancer treatment. Tumor cells undergoing ICD trigger activation of the immune system, as a vaccine. Aims: This study aimed to evaluate ICD induction by TRL. Main methods: Cell viability was evaluated by SRB assay. Cell stress, cell death, ICD features and antigenpresenting molecules were evaluated by flow cytometry and immunoblot. Key findings: TRL showed antiproliferative activity on 7 tumor cell lines (L929, HCT 116, B16-F10, WM293A, SKMEL-28, PC-3M, and MCF-7) and a non-tumor cell (HEK293A), with an inhibition concentration mean (IC50) ranging from 0.03 mu M to 13 mu M. Metastatic melanomas, SK-MEL-28, B16-F10, and WM293A, were more sensitive cell lines, with IC50 ranging from 0.07 to 1.2 mu M. TRL induced apoptosis along with autophagy and endoplasmic reticulum stress and release of typical damage-associated molecular patterns (DAMPs) of ICD such calreticulin, ERp57, and HSP70 exposure, and HMGB1 release. Additionally, melanoma B16-F10 exposed to TRL increased expression of antigen-presenting molecules MHC II and CD1d and induced activation of splenocytes of C57BL/6 mice. Significance: In spite of recent advances provided by target therapy and immunotherapy, advanced metastatic melanoma is incurable for more than half of patients. ICD inducers yield better and long-lasting responses to anticancer treatment. Our findings shed light on an anticancer candidate of marine origin that induces ICD in melanoma.