Research ArticleCancer

Mitochondrial metabolic reprogramming controls the induction of immunogenic cell death and efficacy of chemotherapy in bladder cancer

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Science Translational Medicine  06 Jan 2021:
Vol. 13, Issue 575, eaba6110
DOI: 10.1126/scitranslmed.aba6110

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A chemo drug’s immune side

Mitomycin C is a chemotherapy drug that was discovered years ago and is part of clinical care for bladder cancer and other tumor types. Despite its ongoing clinical use, the mechanism of action of this drug is not entirely understood, and as with any cancer therapy, only some of the patients respond to the treatment. By studying preclinical models with treatment schedules resembling those used in the clinic to treat bladder cancer, Oresta et al. demonstrated that mitomycin C causes metabolic alterations in the tumor cells. These alterations result in cytoplasmic release of mitochondrial DNA, causing inflammasome activation and promoting immunogenic cell death.

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.

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