Mechanisms of Neoantigen-Targeted Induction of Pyroptosis and Ferroptosis: From Basic Research to Clinical Applications

Yu, Jie; Wang, Qing; Zhang, Xiaoyun; Guo, Zhiliang; Cui, Xiaodong

doi:10.3389/fonc.2021.685377

Cited by 11 publications

(11 citation statements)

References 93 publications

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“…Ferroptosis has been reported to modulate the TME to inhibit tumor progression and improve prognosis (19,20). Our study first developed a novel risk-scoring model based on 5 ferroptosis-related prognostic genes from SCLC data from the cBioPortal dataset.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence suggests that activation of ferroptosis can overcome tumor development and reduce the sensitivity of the tumor to chemotherapy ( 8 ). Ferroptosis has been reported to modulate the TME to inhibit tumor progression and improve prognosis ( 19 , 20 ). Our study first developed a novel risk-scoring model based on 5 ferroptosis-related prognostic genes from SCLC data from the cBioPortal dataset.…”

Section: Discussionmentioning

confidence: 99%

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Identification and validation of a ferroptosis-related prognostic risk-scoring model and key genes in small cell lung cancer

Li¹,

Qiu²,

Wu³

et al. 2022

Transl Lung Cancer Res

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Background: Small cell lung cancer (SCLC) is an aggressive lung malignancy with high relapse rates and poor survival outcomes. Ferroptosis is a recently identified type of cell death caused by excessive intracellular iron accumulation and lipid peroxidation, which may mediate tumor-infiltrating immune cells to influence anti-cancer immunity. But prognostic value of ferroptosis-related genes and its relationship with the treatment response of immunotherapies in SCLC have not been elucidated. Methods:The RNA-sequencing and clinical data of SCLC patients were downloaded from the cBioPortal database. A ferroptosis-related prognostic risk-scoring model was constructed based on univariable and multivariable Cox-regression analysis. Kaplan-Meier (K-M) survival curves and receiver operating characteristics (ROC) curves were constructed to assess the sensitivity and specificity of the risk-scoring model. And the correlations between ferroptosis-related prognostic genes and immune microenvironment were explored. The IC50 values of anti-cancer drugs were downloaded from the Genomics of Drug Sensitivity in Cancer (GDSC) database and the correlation analysis with the key gene thioredoxin-interacting protein (TXNIP) was performed. In addition, immunohistochemistry (IHC) staining was employed to detect the expression of TXNIP in 20 SCLC patients who received first-line chemo-immunotherapy.Immunotherapeutic response according to iRECIST (Response Evaluation Criteria in Solid Tumours for immunotherapy trials) were recorded.Results: We constructed a risk-score successfully dividing patients in the low-and high-risk groups (with better and worse prognosis, respectively). The area under the curve (AUC) of this risk-scoring model was 0.812, showing it had good utility in predicting the prognosis of SCLC. Moreover, ferroptosis-related genes were associated with the degree of immune infiltration of SCLC. Most importantly, we found that the TXNIP expression was highly correlated with the degree of immune invasion and the efficacy of chemotherapy in combination with immunotherapy in SCLC patients. Conclusions:The ferroptosis-related prognostic risk-scoring model proposed in this study can potentially predict the prognosis of SCLC patients. TXNIP may serve as a potential biomarker to predict the prognosis and efficacy of chemotherapy combined with immunotherapy in SCLC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification and validation of a ferroptosis-related prognostic risk-scoring model and key genes in small cell lung cancer

Li¹,

Qiu²,

Wu³

et al. 2022

Transl Lung Cancer Res

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“…Blocking CTLA-4 and PD-1 immunotherapies became a crucial part of cancer therapy [ 42 ]. For this purpose, PD-1 (CD279)/PD-L1 (CD274) and CTLA-4 expression were assessed.…”

Section: Resultsmentioning

confidence: 99%

“…Developing new approaches to boost anti-tumor immunity is critical because many tumors are non-responsive to immunotherapy due to a lack of tumor-infiltrating immune cells or tumor-released antigens. The emerging view suggests that pyroptosis releases inflammatory mediators and could alter TME through the influx of immune cells and eliciting tumor antigens [ 42 ]. This study indicated that the pyroptosis modification pattern was strongly correlated to TME, TMB, and the response to the anti-PD-1/L1 immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of pyroptosis regulation patterns and their influence on tumor immune microenvironment and patient prognosis in glioma

et al. 2022

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Background Glioma is the most common intracranial malignancy with a poor prognosis. Although remarkable advances have been made in the study of diagnostic and prognostic biomarkers, the efficacy of current treatment strategies is still unsatisfactory. Therefore, developing novel and reliable targets is desperately needed for glioma patients. Pyroptosis reshapes tumor immune microenvironment (TME) and promotes the destruction of the tumor by the immune system. Moreover, pyroptosis levels correlate with prognosis and immunotherapy response in many cancer patients. This study performed a comprehensive analysis of pyroptosis in the glioma, unveiling its potential value in glioma prognosis prediction and therapy efficacy. Methods Firstly, the pyroptosis regulation patterns were comprehensively evaluated on 33 pyroptosis-related genes in 1716 glioma samples. The correlations were analyzed between pyroptosis regulation patterns and TME immune cell infiltration properties. Next, pyroptosis regulation patterns were measured by the PSscore model based on principal component analysis algorithms. The correlations were analyzed between PSscore and tumor mutational burden (TMB), immune checkpoint blockade (ICB) therapeutic advantages. Last, the findings were validated in an independently collected external clinical cohort. Results We determined two distinct pyroptosis regulation patterns. The cluster-A was high immune cell infiltration with a poor prognosis (p < 0.001), whereas the cluster-B was low immune cell infiltration with a better prognosis (p < 0.001). We developed the PSscore as a measure for pyroptosis regulation patterns. The high PSscore with an inflamed TME phenotype, a high TMB (p < 0.0001), increased innate immune response, and a poor prognosis (p < 0.001). It was in stark contrast to the low PSscore (p < 0.001). Analysis of PSscore with checkpoint therapy indicated high PSscore were correlated with enhanced response to anti-PD-1 immunotherapy (p = 0.0046). For validation, we utilized in vitro experiments on an external clinical cohort. The results demonstrated that GSDMD expression level in the high PSscore group was significantly upregulated compared to the low PSscore group (p < 0.001); the CD3+ T cells and the CD3+PD-1+ cells significantly increased in the high PSscore group compared to the low PSscore group (p < 0.01). Conclusions The PSscore of pyroptosis regulation pattern is a reliable biomarker, and it is valuable to predict prognosis, TME, and ICB therapeutic efficiency in glioma patients.

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“…Historically, three processes of cell death were characterized: apoptosis, necrosis, and autophagy. During the past decade or so, new types of cell death such as pyroptosis and ferroptosis have been identified and their importance gradually appreciated ( Yu et al, 2021 ). Indeed, there is growing evidence for a Ca 2+ related mechanism in ferroptosis in cancerous and noncancerous cells ( Chen P. et al, 2020 ; Angelova et al, 2020 ), suggesting a unique yet ubiquitous role of Ca 2+ in general cell death processes.…”

Section: Stim and Orai In Cell Survivalmentioning

confidence: 99%

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

2022

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Tight spatiotemporal regulation of intracellular Ca2+ plays a critical role in regulating diverse cellular functions including cell survival, metabolism, and transcription. As a result, eukaryotic cells have developed a wide variety of mechanisms for controlling Ca2+ influx and efflux across the plasma membrane as well as Ca2+ release and uptake from intracellular stores. The STIM and Orai protein families comprising of STIM1, STIM2, Orai1, Orai2, and Orai3, are evolutionarily highly conserved proteins that are core components of all mammalian Ca2+ signaling systems. STIM1 and Orai1 are considered key players in the regulation of Store Operated Calcium Entry (SOCE), where release of Ca2+ from intracellular stores such as the Endoplasmic/Sarcoplasmic reticulum (ER/SR) triggers Ca2+ influx across the plasma membrane. SOCE, which has been widely characterized in non-excitable cells, plays a central role in Ca2+-dependent transcriptional regulation. In addition to their role in Ca2+ signaling, STIM1 and Orai1 have been shown to contribute to the regulation of metabolism and mitochondrial function. STIM and Orai proteins are also subject to redox modifications, which influence their activities. Considering their ubiquitous expression, there has been increasing interest in the roles of STIM and Orai proteins in excitable cells such as neurons and myocytes. While controversy remains as to the importance of SOCE in excitable cells, STIM1 and Orai1 are essential for cellular homeostasis and their disruption is linked to various diseases associated with aging such as cardiovascular disease and neurodegeneration. The recent identification of splice variants for most STIM and Orai isoforms while complicating our understanding of their function, may also provide insight into some of the current contradictions on their roles. Therefore, the goal of this review is to describe our current understanding of the molecular regulation of STIM and Orai proteins and their roles in normal physiology and diseases of aging, with a particular focus on heart disease and neurodegeneration.

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Mechanisms of Neoantigen-Targeted Induction of Pyroptosis and Ferroptosis: From Basic Research to Clinical Applications

Cited by 11 publications

References 93 publications

Identification and validation of a ferroptosis-related prognostic risk-scoring model and key genes in small cell lung cancer

Identification and validation of a ferroptosis-related prognostic risk-scoring model and key genes in small cell lung cancer

Comprehensive analysis of pyroptosis regulation patterns and their influence on tumor immune microenvironment and patient prognosis in glioma

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

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