IMMUNOGENIC CELL DEATH AS A NEW MECHANISM OF ACTION OF THE CHEMOTHERAPEUTIC DRUG MITOMYCIN C IN BLADDER CANCER

Despite having been used for more than a century, the exact mechanisms of action, of resistance and the best treatment schedule of most chemotherapeutic agents remain elusive. Mitomycin C (MMC) is the gold standard adjuvant treatment for bladder cancer. However, it is effective only in a proportion of patients, suggesting that, aside from cytotoxicity, other mechanisms could be involved in mediating the success or failure of treatment. We hypothesized that MMC might induce immunogenic cell death (ICD), leading to an antitumor immune response. Here, we describe that MMC fosters ICD via the exposure of damage signals, increased phagocytosis by dendritic cells (DCs) and in vivo tumor protection. MMC-induced ICD relies on the cytoplasmic release of mitochondrial DNA that activates the inflammasome for efficient IL-1β secretion that promotes DC maturation. We found the ICD resistant cancer cells fail to generate an inflammatory microenvironment and display mitochondria dysfunction related to low expression of mitochondrial Complex I of the respiratory chain, which is associated with drug resistance in bladder cancer patients. The identification of ICD as a novel immune-related mechanism of action of MMC provides opportunities to optimize bladder cancer management and identify ICD-related biomarkers of treatment efficacy.