膀胱癌
化疗
程序性细胞死亡
癌症研究
细胞凋亡
医学
免疫原性细胞死亡
重编程
癌症
免疫疗法
肿瘤科
生物
免疫学
细胞
内科学
生物化学
遗传学
作者
Bianca Oresta,Chiara Pozzi,Daniele Braga,Rodolfo Hurle,Massimo Lazzeri,Piergiuseppe Colombo,Nicola Frego,Marco Erreni,Cristina Faccani,Grazia Maria Elefante,Matteo Barcella,Giorgio Guazzoni,María Rescigno
标识
DOI:10.1126/scitranslmed.aba6110
摘要
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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