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Succinate in the tumor microenvironment affects tumor growth and modulates tumor associated macrophages

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Abstract

Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene succinate (PES) microparticles (MPs) biomaterial mediated controlled delivery of succinate in the TME modulates macrophage responses. Administering PES MPs locally with or without a BRAF inhibitor systemically in an immune-defective aging mice with clinically relevant BRAFV600E mutated YUMM1.1 melanoma decreased tumor volume three-fold. PES MPs in the TME also led to maintenance of M1 macrophages with up-regulation of TSLP and type 1 interferon pathway. Impressively, this led to generation of pro-inflammatory adaptive immune responses in the form of increased T helper type 1 and T helper type 17 cells in the TME. Overall, our findings from this challenging tumor model suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.

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... More broadly, ontological pathway databases would likely benefit from separating the leucine, isoleucine, and valine catabolic entries to prevent statistical muting introduced from signature-based analyses, which often group BCAA degradation as a singular process. Succinate has been identified as having many prooncogenic roles, including HIF1α stabilisation [27,28], alteration of the tumour microenvironment [32], promotion of metastatic potential via enhanced EMT [29], suppression of anti-tumour immune responses [33,34] and the activation of pro-inflammatory signalling pathways [35]. Future directions should investigate the effects of HIBCH inhibition on these processes. ...
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... It is not important that the induced intense oxidation of succinate in mitochondria under hypoxic loads, which often accompany pathological conditions, is accompanied by a significant increase in the production of free radicals and mitochondrial dysregulation processes [89]. The succinatedependent metabolism pathways during ageing and pathologies with a varied genesis are shown in Table 2. Analysis of postoperative cognitive dysfunction processes, gerontological patients after cardiac surgery, and a cognitive impairment model, people over 60 years of age, Cytoflavin containing succinic acid Cytoflavin containing inosine, nicotinamide, riboflavin, and succinic acid was used in elderly postoperative patients in a multicenter, double-blind, placebo-controlled, and randomised study Improvement of gerontological patients' condition [121] Study of steroidogenic adrenocortical cells in LPS-induced systemic inflammation processes in a murine model, succinate-succinate dehydrogenase relationship Increased succinate levels by disruption of oxidative phosphorylation and increased ATP synthesis connected with high ROS production SDHB expression via upregulation of DNA methyltransferase 1 and methylation processes in the SDHB promoter [122] Review analysis of the physiological and pathophysiological condition connected with succinic acid metabolism and SDH functions Succinate functions and hypoxia-inducible factor (HIF)-1α, development of pseudohypoxia and tumours via mutated SDH, succinate functions in metabolic or non-metabolic pathways, lysine succinylation process as proteins and immunomodulatory modification levels, blood formation or haematopoiesis Activation of succinate receptor 1 (SUCNR1), G protein-coupled receptor 91 (GPR91), or hypoxia-inducible factor-1α, (HIF)-1α [112] In vivo ischaemia-reperfusion of heart in an open-chest mouse model, metabolomic analysis of ex vivo Langendorff heart experiments Study of succinate-dependent mitochondrial superoxide production in myoblasts Inhibition of ischaemic succinate accumulation and its oxidation as an effective way in ischaemia-reperfusion conditions [123] Immune-defective ageing murine model, clinically relevant BRAF V600E mutated YUMM1.1 melanoma tumour model, cancer immunotherapies Tumour microenvironment study using polyethylene succinate microparticle biomaterial Succinate-mediated immune and cancer cell responses in a tumour model and immunotherapies [124] Hippocampus of different aged APP/PS1 double transgenic AD mice, analysis of the β-amyloid level with the immunohistochemistry method 3, 6, 9, and 12-month-old mice groups, learning and memory test analysis, mitochondrial damage, and autophagosome accumulation assays Abnormal accumulation of succinic acid and citric acid associated with age-related damage to hippocampal mitochondria in the APP/PS1 murine model [125] ...
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The tumor microenvironment is a complex ecology of cells that evolves with and provides support to tumor cells during the transition to malignancy. Among the innate and adaptive immune cells recruited to the tumor site, macrophages are particularly abundant and are present at all stages of tumor progression. Clinical studies and experimental mouse models indicate that these macrophages generally play a protumoral role. In the primary tumor, macrophages can stimulate angiogenesis and enhance tumor cell invasion, motility, and intravasation. During monocytes and/or metastasis, macrophages prime the premetastatic site and promote tumor cell extravasation, survival, and persistent growth. Macrophages are also immunosuppressive, preventing tumor cell attack by natural killer and T cells during tumor progression and after recovery from chemo- or immunotherapy. Therapeutic success in targeting these protumoral roles in preclinical models and in early clinical trials suggests that macrophages are attractive targets as part of combination therapy in cancer treatment.
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Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a crucial role in adenosine triphosphate (ATP) generation in mitochondria. Recently, new roles for succinate outside metabolism have emerged. Succinate stabilizes the transcription factor hypoxia-inducible factor-1α (HIF-1α) in specific tumors and in activated macrophages, and stimulates dendritic cells via its receptor succinate receptor 1. Furthermore, succinate has been shown to post-translationally modify proteins. This expanding repertoire of functions for succinate suggests a broader role in cellular activation. We review the new roles of succinate and draw parallels to other metabolites such as NAD(+) and citrate whose roles have expanded beyond metabolism and into signaling.
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As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses that involve multiple immune and non-immune cell types and that vary depending on the cell activation state and tissue context. This ageing-associated basal inflammation, particularly in humans, is thought to be induced by several factors, including the reactivation of latent viral infections and the release of endogenous damage-associated ligands of pattern recognition receptors (PRRs). Innate immune cell functions that are required to respond to pathogens or vaccines, such as cell migration and PRR signalling, are also impaired in aged individuals. This immune dysregulation may affect conditions associated with chronic inflammation, such as atherosclerosis and Alzheimer's disease.
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Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. Inflammation also affects immune surveillance and responses to therapy. Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, and some of the molecular events that mediate this dialog have been revealed. This review outlines the principal mechanisms that govern the effects of inflammation and immunity on tumor development and discusses attractive new targets for cancer therapy and prevention.
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Metazoan organisms are dependent on a continuous supply of O(2) for survival. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in development, physiology, and disease. HIF-1 activity is induced in response to continuous hypoxia, intermittent hypoxia, growth factor stimulation, and Ca(2+) signaling. HIF-1 mediates adaptive responses to hypoxia, including erythropoiesis, angiogenesis, and metabolic reprogramming. In each case, HIF-1 regulates the expression of multiple genes encoding key components of the response pathway. HIF-1 also mediates maladaptive responses to chronic continuous and intermittent hypoxia, which underlie the development of pulmonary and systemic hypertension, respectively.
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While tumour incidence is known to augment with age, paradoxically tumour growth and metastasis were often found to proceed at a slower rate at late ages. This age-related biological behaviour of tumours actually imposes a differential therapeutic approach to the old cancer patient. Several mechanisms of the age-related reduced tumour progression have been demonstrated: decreased tumour cell proliferation, increased apoptotic cell death, decreased angiogenesis and anti-tumoural immune response changes. We postulated that it might be possible to design age-adjusted treatment modalities based on the mechanisms responsible for the reduced tumour progression rate in the aged. Based on these mechanisms, we compared the effect of different treatments (apoptosis-inducing agents, Hydrocortisone and Adriamycin, anti-angiogenic agent, TNP-470, and immunomodulators-Levamisole and BCG) on two experimental tumours (B16 melanoma and AKR lymphoma) growing in young and old mice. Most treatments showed, in both tumours, a higher inhibitory effect on tumours growing in old mice than on those developing in young ones, to our knowledge, a feature not described before for anti-tumoural agents. We suggest that designing ageing conditions in tumours of young patients might possibly alleviate neoplastic aggressiveness in these patients as well.