Figure - available from: Cancer Immunology and Immunotherapy
This content is subject to copyright. Terms and conditions apply.
![Formation and degradation of itaconic acid. Itaconic acid is a dicarboxylic acid formed by the decarboxylation of cis-aconitate, a component of the citric acid cycle. This reaction is mediated by the gene product of bacterial Acod1 (aconitate decarboxylase 1) or mammalian Irg1 (immune-responsive gene 1). Itaconic acid mediates immunosuppression by multiple pathways (reviewed in [37]). It inhibits succinate dehydrogenase (SDH), resulting in succinate accumulation and suppression of ROS and pro-inflammatory cytokine expression upon cell activation. Itaconic acid also activates NRF2 which may also reduce ROS and IL-1β expression. The breakdown or catabolism of itaconic acid involves its conversion into itaconyl-CoA by Ict (itaconate CoA transferase) or succinate-CoA ligase and further processing into pyruvate and acetyl-CoA [32, 46]](publication/337606505/figure/fig3/AS:941421435580426@1601463769414/Formation-and-degradation-of-itaconic-acid-Itaconic-acid-is-a-dicarboxylic-acid-formed.png)
Formation and degradation of itaconic acid. Itaconic acid is a dicarboxylic acid formed by the decarboxylation of cis-aconitate, a component of the citric acid cycle. This reaction is mediated by the gene product of bacterial Acod1 (aconitate decarboxylase 1) or mammalian Irg1 (immune-responsive gene 1). Itaconic acid mediates immunosuppression by multiple pathways (reviewed in [37]). It inhibits succinate dehydrogenase (SDH), resulting in succinate accumulation and suppression of ROS and pro-inflammatory cytokine expression upon cell activation. Itaconic acid also activates NRF2 which may also reduce ROS and IL-1β expression. The breakdown or catabolism of itaconic acid involves its conversion into itaconyl-CoA by Ict (itaconate CoA transferase) or succinate-CoA ligase and further processing into pyruvate and acetyl-CoA [32, 46]
Source publication
A major challenge of cancer immunotherapy is the potential for undesirable effects on bystander cells and tumor-associated immune cells. Fundamentally, we need to understand what effect targeting tumor metabolism has upon the metabolism and phenotype of tumor-associated leukocytes, whose function can be critical for effective cancer therapeutic str...
Similar publications
Macrophage activation is intimately linked to metabolic reprogramming. Inflammatory (M1) macrophages are able to sustain inflammatory responses and to kill pathogens, mostly by relying on aerobic glycolysis and fatty acid biosynthesis. Glycolysis is a fast way of producing ATP, and fatty acids serve as precursors for the synthesis of inflammatory m...
![Monitoring of the metabolic fate of [6,6-²H2]glucose by ²H MRS. (A)...](publication/374271539/figure/fig3/AS:11431281254807180@1719302964155/Monitoring-of-the-metabolic-fate-of-6-6-H2glucose-by-H-MRS-A-Scheme-of-the_Q320.jpg)
Background
Inflammation and metabolism exhibit a complex interplay, where inflammation influences metabolic pathways, and in turn, metabolism shapes the quality of immune responses. Here, glucose turnover is of special interest, as proinflammatory immune cells mainly utilize glycolysis to meet their energy needs. Noninvasive approaches to monitor b...
Background
Dysfunction of CD8⁺ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8⁺ T cells might differentially associate with dysfunction. However, specific parameters a...
Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components. The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells. Macrophages are embryo- or adult bone marrow-derived leukoc...
The search for bioactive compounds from enzymatic hydrolysates has increased in the last few decades. Fish by-products have been shown to be rich in these valuable molecules; for instance, herring milt is a complex matrix composed of lipids, nucleotides, minerals, and proteins. However, limited information is available on the potential health benef...
Citations
... This may be because many cancer cells are still reproducing during the treatment period. Most cells rely on glycolysis to produce energy (the Wahlberg effect) [42,43], and the RE intervention at this time would be more beneficial for inhibiting the activity of cancer cells. After cancer treatment, the number of cancer cells in the body is significantly reduced to the point where there are no longer any cancer cells. ...
Background
Physical activity is associated with improved health-related quality of life (HRQoL) in breast cancer survivors (BCS); however, no studies have assessed optimal physical activity.
Objective
We aimed to investigate the optimal types of physical activity for improving HRQoL in patients with BCS during and after cancer treatment.
Methods
A comprehensive search was conducted in Medline, Embase, Web of Science, and Cochrane Library from inception to November 2023. We included randomized controlled trials (RCTs) reporting the effects of different physical activities on HRQoL in BCS. Two independent reviewers assessed the risk of bias using the Cochrane risk of bias tool for randomized trials (version 2.0). A network meta-analysis approach based on a frequentist framework was used to rank the effectiveness of different physical activities.
Results
A total of 66 RCTs with 6464 participants were included. For all BCS, aerobic combined with resistance exercise (CE) (standardized mean difference [SMD] = 0.71; 95 % confidence interval [CI]: 0.40 to 1.10; P-score = 0.75; Grade: moderate) was the most effective physical activity to improve HRQoL. For participants in treatment, resistance exercise (RE) (SMD = 0.68; 95 % CI: 0.35 to 1.10; P-score = 0.84; Grade: moderate) was the most effective. However, after treatment, CE (SMD = 0.77; 95 % CI: 0.28 to 1.26; P-score = 0.74; Grade: very low) remained the most effective way to improve HRQoL in BCS. In addition, the regression analysis did not find any sources of heterogeneity.
Conclusions
The findings of this study suggest that all physical activities improved HRQoL in BCS compared to the control group. CE may have the best effect on all survivors and post-treatment survivors, whereas RE has the best effect during treatment. In addition, the quality of the included studies was low, and there was some risk of bias, which may affect the interpretation of the findings.
... Metabolism is another potential vulnerability, as tumor cells alter normal cellular metabolism to support their high demand for energy and generation of biomass to support growth and proliferation (8,9). This finding has led to a growing interest in identifying metabolic therapies as an alternative strategy for targeting cancer (10)(11)(12)(13). However, a confounding issue with metabolic therapies is toxicity. ...
Identifying and leveraging unique points of metabolic dysregulation in different disease settings is vital for safe and effective incorporation of metabolism-targeted therapies in the clinic. In addition, it has been shown identification of master metabolic transcriptional regulators (MMTR) of individual metabolic pathways, and how they relate to the disease in question, may offer the key to understanding therapeutic response. In prostate cancer, we have previously demonstrated polyamine biosynthesis and the methionine cycle were targetable metabolic vulnerabilities. However, the MMTRs of these pathways, and how they affect treatment, have yet to be explored. We sought to characterize differential sensitivity of prostate cancer to polyamine- and methionine-targeted therapies by identifying novel MMTRs. We began by developing a gene signature from patient samples, which can predict response to metabolic therapy, and further uncovered a MMTR, JAZF1. We characterized the effects of JAZF1 overexpression on prostate cancer cells, basally and in the context of treatment, by assessing mRNA levels, proliferation, colony formation capability, and key metabolic processes. Lastly, we confirmed the relevance of our findings in large publicly available cohorts of prostate cancer patient samples. We demonstrated differential sensitivity to polyamine and methionine therapies and identified JAZF1 as a MMTR of this response.
Implications
We have shown JAZF1 can alter sensitivity of cells and its expression can segregate patient populations into those that do, or do not highly express polyamine genes, leading to better prediction of response to a polyamine targeting therapy.
... THP-1 M1 macrophages increased etoposide-induced cancer cell apoptosis, while M2 macrophages decreased apoptosis of cells (158). Recently, researchers found that itaconic acid is one attractive candidate for anti-tumor responses, since peritoneal tumors could be controlled by specifically targeting resident macrophage-associated itaconate levels (159). Although precise regulation is unclear, the targeting of resident macrophages is a potential perspective for future research. ...
Macrophages are versatile immune cells associated with various diseases, and their phenotypes and functions change on the basis of the surrounding environments. Reprogramming of metabolism is required for the proper polarization of macrophages. This review will focus on basic metabolic pathways, the effects of key enzymes and specific products, relationships between cellular metabolism and macrophage polarization in different diseases and the potential prospect of therapy targeted key metabolic enzymes. In particular, the types and characteristics of macrophages at the maternal-fetal interface and their effects on a successful conception will be discussed.
... In accordance with this, increasing evidence shows dysregulated cellular signaling and metabolism in myeloid cell subsets that infiltrate immunologically cold tumors resistant to immune checkpoint inhibitors (ICIs), chemo-and radio-therapy, characterized by a lack in T and NK cell infiltrates, and the accumulation of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and tolerogenic dendritic cells (DCs) [8,9]. ...
Simple Summary
Immunotherapy is achieving impressive results in the treatment of several cancers. While the main strategies aim to re-invigorate the specific lymphocyte anti-tumor response, many studies underline that altered myeloid cell frequency and functions can dramatically interfere with the responsiveness to cancer therapies. Therefore, many novel strategies targeting TAMs and MDSCs in combination with classical treatments are under continuous evolution at both pre-clinical and clinical levels, showing encouraging results. Herein, we depict a comprehensive overview of myeloid cell generation and function in a cancer setting, and the most relevant strategies for their targeting that are currently in clinical use or under pre-clinical development.
Abstract
In recent years, the immune system has emerged as a critical regulator of tumor development, progression and dissemination. Advanced therapeutic approaches targeting immune cells are currently under clinical use and improvement for the treatment of patients affected by advanced malignancies. Among these, anti-PD1/PD-L1 and anti-CTLA4 immune checkpoint inhibitors (ICIs) are the most effective immunotherapeutic drugs at present. In spite of these advances, great variability in responses to therapy exists among patients, probably due to the heterogeneity of both cancer cells and immune responses, which manifest in diverse forms in the tumor microenvironment (TME). The variability of the immune profile within TME and its prognostic significance largely depend on the frequency of the infiltrating myeloid cells, which often represent the predominant population, characterized by high phenotypic heterogeneity. The generation of heterogeneous myeloid populations endowed with tumor-promoting activities is typically promoted by growing tumors, indicating the sequential levels of myeloid reprogramming as possible antitumor targets. This work reviews the current knowledge on the events governing protumoral myelopoiesis, analyzing the mechanisms that drive the expansion of major myeloid subsets, as well as their functional properties, and highlighting recent translational strategies for clinical developments.
... Drugs targeting glycolytic inhibition repress tumor progression. 57 The notion that repression of autophagy and/or glycolysis has to be taken into consideration to complete cancer cell apoptosis might give us a better idea for developing cancer therapy in the future. ...
Purpose
The mechanism of cytotoxicity of silibinin on two human hepatocellular carcinoma (HCC) cell lines, HepG2 (p53 wild-type) and Hep3B cells (p53 null), is examined in relation with the induction of autophagy and phosphorylation of AMP-activated protein kinase (p-AMPK).
Materials and Methods
Levels of apoptosis in relation to the levels of autophagy and those of glycolysis-related proteins, glucose transporter 1/4 (Glut1/4) and hexokinase-II (HK2), in HepG2 and Hep3B cells were examined.
Results
Silibinin-induced apoptosis was incomplete for HCC cell death in that up-regulated autophagy and/or reduced level of glycolysis, which are induced by silibinin treatment, antagonized silibinin-induced apoptosis. Inhibition of autophagy with 3-methyl adenine (3MA) or blocking of AMP-activated protein kinase (AMPK) activation with Compound C (CC) enhanced silibinin-induced apoptosis. The results confirm that AMPK involved in autophagy as well as in glycolysis remaining with silibinin is responsible for attenuation of silibinin-induced apoptosis. Blocking of AMPK or autophagy contributes to the enhancement of silibinin’s cytotoxicity to HepG2 and Hep3B cells.
Conclusion
This study shows that incomplete apoptosis of HCC by silibinin treatment becomes complete by repression of autophagy and/or glycolysis.
... This competition for nutrients, together with the lactate-induced acidosis, make the TME favorable for TILs, TAMs and MDSCs, and unsuitable for effector cells, thus promoting immune evasion. TILs and TAMs have anti-inflammatory phenotypes and either secrete or induce factors that promote immunosuppression and tumor invasion, such as interleukin-10 (Il-10), TGF-β, PD-1, reactive oxygen species (ROS) and arginase [40,43,49,65,[76][77][78][79][80] (Fig. 2). ...
Osteosarcoma (OS) is the most frequent primary bone cancer, affecting mostly children and adolescents. Although much progress has been made throughout the years towards treating primary OS, the 5-year survival rate for metastatic OS has remained at only 20% for the last 30 years. Therefore, more efficient treatments are needed. Recent studies have shown that tumor metabolism displays a unique behavior, and plays important roles in tumor growth and metastasis, making it an attractive potential target for novel therapies. While normal cells typically fuel the oxidative phosphorylation (OXPHOS) pathway with the products of glycolysis, cancer cells acquire a plastic metabolism, uncoupling these two pathways. This allows them to obtain building blocks for proliferation from glycolytic intermediates and ATP from OXPHOS. One way to target the metabolism of cancer cells is through dietary interventions. However, while some diets have shown anticancer effects against certain tumor types in preclinical studies, as of yet none have been tested to treat OS. Here we review the features of tumor metabolism, in general and about OS, and propose avenues of research in dietary intervention, discussing strategies that could potentially be effective to target OS metabolism.
... Oncogene activation and tumor suppressor gene (TSG) inactivation can result in uncontrolled cell proliferation, known as cancer (Weiss, 2020). The tumor structure consists of cells that carry changes in the genes that regulate growth and differentiation (Croce, 2008). ...
The assembly of stress granules (SGs) is a well-known cellular strategy for reducing stress-related damage and promoting cell survival. SGs have become important players in human health, in addition to their fundamental role in the stress response. The critical role of SGs in cancer cells in formation, progression, and metastasis makes sense. Recent researchers have found that several SG components play a role in tumorigenesis and cancer metastasis via tumor-associated signaling pathways and other mechanisms. Gene-ontology analysis revealed the role of these protein components in the structure of SGs. Involvement in the translation process, regulation of mRNA stability, and action in both the cytoplasm and nucleus are among the main features of SG proteins. The present scoping review aimed to consider all studies on the effect of SGs on cancer formation, proliferation, and metastasis and performed based on a six-stage methodology structure and the PRISMA guideline. A systematic search of seven databases for qualified articles was conducted before July 2021. Publications were screened, and quantitative and qualitative analysis was performed on the extracted data. Go analysis was performed on seventy-one SGs protein components. Remarkably G3BP1, TIA1, TIAR, and YB1 have the largest share among the proteins considered in the studies. Altogether, this scoping review tries to demonstrate and provide a comprehensive summary of the role of SGs in the formation, progression, and metastasis of cancer by reviewing all studies.
... Research shows that the infiltration of immune cells in tumors is closely related to clinical outcomes. Immune cells infiltrated in tumors are most likely to serve as drug targets to improve patient survival (7) as they can be isolated after migrating from blood to tissue (8). However, it is difficult to analyze tumor prognosis with gene methylation combined with tumor immune infiltration, and few studies have reported it. ...
Background:
Glioblastoma multiforme (GBM) is the most aggressive and malignant tumor of the central nervous system. The study was to obtain the data of immune cell infiltration based on the data of a methylation chip in the GEO, and to clarify its prognostic significance for GBM.
Methods:
The methylation data of glioblastoma was obtained by using the Illumina human methylation 450k BeadChip. The corrected expression was obtained by using edge R. Limma was used to correct the expression amount of the samples, and EpiDISH was used to translate the methylation expression data, so that the expression amount was transformed into the expression matrix of immune cells. The immune cells were then co-expressed, and the proportion and correlation of related immune cells was determined. The results of the cells in each of two groups were analyzed by enrichment and PCA mapping to establish the relevant differences.
Results:
The data of GBM patients were obtained from the methylation chip of the GEO database. Patients were divided into a long-term (SNU-LTS) (21 cases), and short-term survival group (SNU-STS) (12 cases). There were 73 genes with significant individual differences between the two groups (P<0.05). EpiDISH was used to translate the methylation expression data into the expression matrix of immune cells, which showed that the highest proportion of cells in groups were mono cells, while Gran cells and CD8T appeared in a very small number of samples. The positive correlation between mono and B cells was the strongest, while the negative correlation between mono and Gran cells was the strongest. A violin chart shows that there was no significant difference in the infiltration degree of six kinds of immune cells between the two groups. Principal component analysis (PCA) showed that there was individual difference between the two groups, but the overall consistency was high.
Conclusions:
Data on tumor immune cell infiltration can be obtained by using a methylation chip in the GEO database. This not only extends the application abilities of methylation chips but provides obvious individual differences. The study of tumor immune infiltrating cells may pave the way for targeted therapy in the treatment of GBM.
... More broadly, in addition to hematopoietic cell transplantation, abrogation of allo-specific CD4 + and CD8 + T cell immune responses and activation involved by cytokine production and T cell proliferation to setback rejection after solid organ transplantation as well in skin and heart allograft transplantations of mice have been established using combination of 2-deoxy-D-glucose (2-DG), 6-diazo-5-oxo-L-norleucine (DON), which acts as a glutamine metabolism inhibitor and the anti-type II diabetes drug metformin, which acts as an inhibitor of complex I of the electron transport chain (ETC) (Lee et al., 2015;Weiss, 2020;Cameron et al., 2018) (Fig. 3). Moreover, combination with above triple therapy in solid organ transplantation could achieve a considerable suppression effect. ...
Liver transplantation (LT) is the most effective treatment for end-stage liver diseases. The immunometabolism microenvironment undergoes massive changes at the interface of immune functionalities and metabolic regulations after LT. These changes considerably modify post-transplant complications, and immune cells play an influential role in the hepatic immunometabolism microenvironment after LT. Therefore, adequate studies on the complex pathobiology of immune cells are critical to prevent post-transplant complications, and the interplay between cellular metabolism and immune function is evident. Furthermore, immune cells perform their specified functions, such as activation or differentiation, accompanied by alterations in metabolic pathways, such as metabolic reprogramming. This transformation remarkably affects post-transplant complications like rejection. By targeting different metabolic pathways, regulations of metabolism are employed to shape immune responses. These differences of metabolic pathways allow for selective regulation of immune responses to further develop effective therapies that prevent graft loss after LT. This review examines immune cells in the hepatic immuno-metabolism microenvironment after LT, summarizes possible mechanisms and potential prevention on rejection to acquire immune tolerance, and offers some insight into references for scientific research along with clinical treatment.
... The aerobic glycolytic capacity of tumor cells is 20-30 times that of normal cells, which provides a lot of energy and intermediate products for tumor metabolism. Thus, targeting metabolic enzymes in abnormal metabolic pathways such as glycolytic pathway has become the focus of anti-tumor therapy (Gill et al., 2016;Abdel-Wahab et al., 2019;Kim, 2019;Weiss, 2020). Researchers are exploring the abnormal regulation of glucose metabolism in tumors and the inhibitors targeting related metabolic responses so as to facilitate better treatment and prognosis for tumor patients by inhibiting tumor glycolysis or switching to normal metabolic pathways. ...
The Warburg effect (aerobic glycolysis) is a hallmark of cancer and is becoming a promising target for diagnosis and therapy. Phosphoglycerate kinase 1 (PGK1) is the first adenosine triphosphate (ATP)-generating glycolytic enzyme in the aerobic glycolysis pathway and plays an important role in cancer development and progression. However, how microRNAs (miRNAs) regulate PGK1-mediated aerobic glycolysis remains unknown. Here, we show that miR-16-1-3p inhibits PGK1 expression by directly targeting its 3′-untranslated region. Through inhibition of PGK1, miR-16-1-3p suppressed aerobic glycolysis by decreasing glucose uptake, lactate and ATP production, and extracellular acidification rate, and increasing oxygen consumption rate in breast cancer cells. Aerobic glycolysis regulated by the miR-16-1-3p/PGK1 axis is critical for modulating breast cancer cell proliferation, migration, invasion and metastasis in vitro and in vivo. In breast cancer patients, miR-16-1-3p expression is negatively correlated with PGK1 expression and breast cancer lung metastasis. Our findings provide clues regarding the role of miR-16-1-3p as a tumor suppressor in breast cancer through PGK1 suppression. Targeting PGK1 through miR-16-1-3p could be a promising strategy for breast cancer therapy.
