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

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.

Integrated Analysis of Energy Metabolism Signature-Identified Distinct Subtypes of Bladder Urothelial Carcinoma

“…It was found that the immune system could be affected by lactic acid accumulated from the aerobic glycolysis process of tumor cells, which includes the enhancement of cytokine transcription and inhibition of the differentiation of monocytes into dendritic cells ( Becker et al, 2013 ; Ghesquière et al, 2014 ). Oresta et al found that mitochondrial metabolism is reprogrammed to control the induction of immunogenic cell death and the efficacy of chemotherapy for bladder cancer by increasing OXPHOS ( Oresta et al, 2021 ). Our study showed a similar result, in which a significant correlation between metabolic status and resistance to chemotherapy, including doxorubicin and gemcitabine, was observed.…”

Life after Cell Death—Survival and Survivorship Following Chemotherapy

“…Similar metabolic preference has been found in other cancer types, such as human acute myeloid leukaemia [30]. The relationship between metabolic reprogramming and mitochondrial function has recently been underscored by a seminal study elucidating the mechanisms underlying resistance to mitomycin C in bladder cancer, illustrating that both the tumour and context-specificity impact on the success of cytotoxic intervention [31].…”

A Target Animal Effectiveness Study on Adjuvant Peptide-Based Vaccination in Dogs with Non-Metastatic Appendicular Osteosarcoma Undergoing Amputation and Chemotherapy

“…There is evidence that the efficacy of some conventional chemotherapeutics, including platinum compounds, involves not only their cytotoxic effect, but also relies on modulation of the immune system by reducing the numbers of immunosuppressive myeloid cells [ 36 ]. Additionally, tumor cell death triggers a clinically significant immunogenic response [ 37 , 38 , 39 ]. All types of cancer vaccines stand to benefit from chemotherapy combinations [ 40 ]; in this trial, vaccination was started during chemotherapy, yet it did not prevent the mounting of a significant immune response.…”