No abstract

Although chemotherapeutic agents have been used for decades, the mechanisms of action, mechanisms of resistance, and the best treatment schedule remain elusive. Mitomycin C (MMC) is the gold standard treatment for non–muscle-invasive bladder cancer (NMIBC). However, it is effective only in a subset of patients, suggesting that, aside from cytotoxicity, other mechanisms could be involved in mediating the success of the treatment. Here, we showed that MMC promotes immunogenic cell death (ICD) and in vivo tumor protection. MMC-induced ICD relied on metabolic reprogramming of tumor cells toward increased oxidative phosphorylation. This favored increased mitochondrial permeability leading to the cytoplasmic release of mitochondrial DNA, which activated the inflammasome for efficient IL-1β (interleukin-1β) secretion that promoted dendritic cell maturation. Resistance to ICD was associated with mitochondrial dysfunction related to low abundance of complex I of the respiratory chain. Analysis of complex I in patient tumors indicated that low abundance of this mitochondrial complex was associated with recurrence incidence after chemotherapy in patients with NMIBC. The identification of mitochondria-mediated ICD as a mechanism of action of MMC offers opportunities to optimize bladder cancer management and provides potential markers of treatment efficacy that could be used for patient stratification.

No abstract

535 Background: Mounting evidence indicates that the microbiota plays an important role in carcinogenesis and response to treatments. The dogma that urine is sterile has been overturned and dysbiosis of the urinary microbiota has been linked to urological disorders. We tested the hypothesis that alteration in urinary microbial community composition may be associated to bladder cancer development and progression. Therefore, we performed a study to characterize the urinary microbiota associated with non-muscle invasive and muscle invasive bladder cancer (NMIBC, MIBC). Methods: Urines were collected with a catheter from BC patients before transurethral resection or cystectomy, and age-matched non-neoplastic subjects. Subjects with prior history of sexually transmitted infection, chronic intestinal inflammation, urinary tract infection and recent usage of antibiotic or immunomodulatory agents were excluded. Bacterial DNA was extracted and amplified for 16S rDNA sequencing. Results: We isolated bacterial DNA from urine samples of 12 non-neoplastic control subjects and 27 BC patients. The most abundant phyla in both groups were Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria, with Bacteroidetes being slightly more abundant in bladder cancer at the expense of Proteobacteria. Interestingly, we found that NMIBC displayed a reduction in the abundance of Sphingobacteriaceae, Bifidobacteriaceae and Enterobacteriaceae. High grade NMIBC and MIBC showed decreased Bifidobacterium and Ruminococcus, which are known to protect from inflammation, and increased Corynebacterium, a potential opportunistic bacteria. No correlation with environmental risk factors (i.e. smoking) was investigated. Conclusions: The urinary microbiota of BC patients displayed a significantly different pattern relative to control group, suggesting that the tumor microenvironment can influence dysbiosis. In particular, we found specific bacteria to associate with aggressive tumors. A better understanding of the urinary microbiota could pave the way for exploring new therapeutic options based on the manipulation of the microbial community. Analysis of additional samples is ongoing.