Abstract
The anticancer thiosemicarbazone Triapine is currently in a phase III clinical trial in combination with radiation therapy and cisplatin. Noteworthy, while radiotherapy induces an immune-activating cell death, so called immunogenic cell death (ICD), cisplatin possesses immunomodulatory and ICD-enhancing functions. Interestingly, although there are several indications that suggest that Triapine could also enhance the immune recognition of cancer cells, no investigations in this direction have been reported so far. Indeed, immune cells (especially cytotoxic T-cells) were found to enhance the anticancer activity of Triapine. This effect might be based on endoplasmic reticulum (ER) stress induction, which on the one hand led to ICD of the cancer cells as indicated by ATP release, calreticulin exposure, high-mobility group box 1 secretion and in vivo vaccination experiments. On the other hand, the Triapine-induced ER stress resulted in FAS upregulation in cell culture as well as in vivo via NFκB signaling. This, in turn, rendered cancer cells more susceptible to FASL (predominantly expressed by lymphoid immune cells)-induced caspase 8-mediated apoptosis. Consequently, our study is the first to unveil the significant role of the (adaptive) immune system in the anticancer activity of Triapine, positioning it as a promising partner for combination with immunotherapy and other immunogenic agents.