Targeted scavenging of extracellular ROS relieves suppressive immunogenic cell death.
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ABSTRACT:
SUBMITTER: Deng H
PROVIDER: S-EPMC7532538 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:As opposed to the standard tolerogenic apoptosis, immunogenic cell death (ICD) constitutes a type of cellular demise that elicits an adaptive immune response. ICD has been characterized in malignant cells following cytotoxic interventions, such as chemotherapy or radiotherapy. Briefly, ICD of cancer cells releases some stress/danger signals that attract and activate dendritic cells (DCs). The latter can then engulf and cross-present tumor antigens to T lymphocytes, thus priming a cancer-specific immunity. This series of reactions works as a positive feedback loop where the antitumor immunity further improves the therapeutic efficacy by targeting cancer cells spared by the cytotoxic agent. However, not all chemotherapeutic drugs currently approved for cancer treatment are able to stimulate bona fide ICD: some commonly used agents, such as cisplatin or 5-fluorouracil, are unable to activate all features of ICD. Therefore, a better characterization of the process could help identify some gene or protein candidates to target pharmacologically and suggest combinations of drugs that would favor/increase antitumor immune response. To this end, we have built a mathematical model of the major cell types that intervene in ICD, namely cancer cells, DCs, CD8+ and CD4+ T cells. Our model not only integrates intracellular mechanisms within each individual cell entity, but also incorporates intercellular communications between them. The resulting cell population model recapitulates key features of the dynamics of ICD after an initial treatment, in particular the time-dependent size of the different cell types. The model is based on a discrete Boolean formalism and is simulated by means of a software tool, UPMaBoSS, which performs stochastic simulations with continuous time, considering the dynamics of the system at the cell population level with appropriate timing of events, and accounting for death and division of each cell type. With this model, the time scales of some of the processes involved in ICD, which are challenging to measure experimentally, have been predicted. In addition, our model analysis led to the identification of actionable targets for boosting ICD-induced antitumor response. All computational analyses and results are compiled in interactive notebooks which cover the presentation of the network structure, model simulations, and parameter sensitivity analyses.
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Project description:Despite advances in treatments like chemotherapy and radiotherapy, metastatic cancer remains a leading cause of death for cancer patients. While many chemotherapeutic agents can efficiently eliminate cancer cells, long-term protection against cancer is not achieved and many patients experience cancer recurrence. Mobilizing and stimulating the immune system against tumor cells is one of the most effective ways to protect against cancers that recur and/or metastasize. Activated tumor specific cytotoxic T lymphocytes (CTLs) can seek out and destroy metastatic tumor cells and reduce tumor lesions. Natural Killer (NK) cells are a front-line defense against drug-resistant tumors and can provide tumoricidal activity to enhance tumor immune surveillance. Cytokines like IFN-? or TNF play a crucial role in creating an immunogenic microenvironment and therefore are key players in the fight against metastatic cancer. To this end, a group of anthracyclines or treatments like photodynamic therapy (PDT) exert their effects on cancer cells in a manner that activates the immune system. This process, known as immunogenic cell death (ICD), is characterized by the release of membrane-bound and soluble factors that boost the function of immune cells. This review will explore different types of ICD inducers, some in clinical trials, to demonstrate that optimizing the cytokine response brought about by treatments with ICD-inducing agents is central to promoting anti-cancer immunity that provides long-lasting protection against disease recurrence and metastasis.
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Project description:Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.
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Project description:The extracellular pH (pHe) is a key determinant of the cellular (micro)environment and needs to be maintained within strict boundaries to allow normal cell function. Here we used HEK293 cells to study the effects of pHe acidification (24h), induced by mitochondrial inhibitors (rotenone, antimycin A) and/or extracellular HCl addition. Lowering pHe from 7.2 to 5.8 reduced cell viability by 70% and was paralleled by a decrease in cytosolic pH (pHc), hyperpolarization of the mitochondrial membrane potential (Δψ), increased levels of hydroethidine-oxidizing ROS and stimulation of protein carbonylation. Co-treatment with the antioxidant α-tocopherol, the mitochondrial permeability transition pore (mPTP) desensitizer cyclosporin A and Necrostatin-1, a combined inhibitor of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and Indoleamine 2,3-dioxygenase (IDO), prevented acidification-induced cell death. In contrast, the caspase inhibitor zVAD.fmk and the ferroptosis inhibitor Ferrostatin-1 were ineffective. We conclude that extracellular acidification induces necroptotic cell death in HEK293 cells and that the latter involves intracellular acidification, mitochondrial functional impairment, increased ROS levels, mPTP opening and protein carbonylation. These findings suggest that acidosis of the extracellular environment (as observed in mitochondrial disorders, ischemia, acute inflammation and cancer) can induce cell death via a ROS- and mPTP opening-mediated pathogenic mechanism.
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Project description:AimsInterferon-? (IFN-?) exhibits hepatotoxicity through signal transducer and activator of transcription 1 (STAT1) activation. On the contrary, interleukin-11 (IL-11) shows tissue-protective effects on various organs including the liver through STAT3 activation. Here, we found that IL-11 pretreatment protects hepatocytes from IFN-?-induced death and investigated the molecular mechanisms, particularly focusing on signal crosstalk.Methods and resultsPrimary culture mouse hepatocytes were treated with IL-11 prior to IFN-?, and cell death was evaluated by lactate dehydrogenase release into media. As a result, IL-11 pretreatment effectively suppressed IFN-?-induced hepatocyte death. Since IFN-?-induced hepatocyte death requires STAT1 signaling, the activity of STAT1 was analyzed. IFN-? robustly activated STAT1 with its peak at 1 hr after stimulation, which was significantly attenuated by IL-11 pretreatment. Consistently, IL-11 pretreatment impeded mRNA increase of STAT1-downstream molecules promoting cell death, i.e., IRF-1, caspase 1, bak, and bax. IL-11-mediated suppression of STAT1 signaling was presumably due to upregulation of the suppressor of cytokine signaling (SOCS) genes, which are well-known negative feedback regulators of the JAK/STAT pathway. Interestingly, however, IFN-? pretreatment failed to affect the following IL-11-induced STAT3 activation, although IFN-? also upregulated SOCSs. Finally, we demonstrated that IL-11 pretreatment mitigated oxidative stress through increasing expression of ROS scavengers.ConclusionIL-11 protects hepatocytes from IFN-?-induced death via STAT1 signal suppression and ROS scavenging. Further investigation into the mechanisms underlying selective negative feedback regulation of IFN-?/STAT1 signaling compared to IL-11/STAT3 signaling may shed new light on the molecular biology of hepatocytes.
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Project description:It is now clear that the immune system plays a critical role not only during oncogenesis and tumor progression, but also as established neoplastic lesions respond to therapy. Selected cytotoxic chemicals can indeed elicit immunogenic cell death, a functionally peculiar type of apoptosis that stimulates tumor-specific cognate immune responses. Such immunogenic chemotherapeutics include cyclophosphamide, doxorubicin and oxaliplatin (which are approved by FDA for the treatment of various hematological and solid malignancies), mitoxantrone (which is currently employed both as an anticancer agent and against multiple sclerosis) and patupilone (a microtubular poison in clinical development). One year ago, in the second issue of OncoImmunology, we discussed the scientific rationale behind immunogenic chemotherapy and reviewed the status of recent clinical trials investigating the off-label use of cyclophosphamide, doxorubicin, oxaliplatin and mitoxantrone in cancer patients. Here, we summarize the latest developments in this area of clinical research, covering both high-impact studies that have been published during the last 13 months and clinical trials that have been initiated in the same period to assess the antineoplastic profile of immunogenic chemotherapeutics.
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